Patent Publication Number: US-2018050982-A1

Title: Uses of histone acetyltransferase activators

Description:
This application claims priority to U.S. Provisional Application No. 61/495,495, filed on Jun. 10, 2011, the entirety of which is incorporated herein by reference. 
    
    
     GOVERNMENT SUPPORT 
     This invention was made with government support under R01 - NS049442 awarded by the National Institute of Neurological Disorders and Stroke (NINDS), and under AG034248 awarded by the National Institute of Aging (NIA). The government has certain rights in the invention. 
    
    
     All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. 
     This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights. 
     BACKGROUND OF THE INVENTION 
     Cognitive neurodegenerative disorders are characterized by synaptic dysfunction, cognitive abnormalities, and/or the presence of inclusion bodies throughout the CNS containing, for example, but not limited to native beta-amyloid fragments, native and phosphorylated Tau, native and phosphorylated alpha-synuclein, lipofuscin, cleaved TARDBP (TDB-43), in various percentages and in relation to the specific disease. Alzheimer&#39;s disease (AD) is one of the most prevalent neurodegenerative disorders characterized by memory loss, and significant research toward discovering treatment for this devastating disease has been undertaken. 
     Cognitive disorders that are not neurodegenerative, such as normal memory loss, as well as neurocognitive enhancement of normal individuals has become of increasing interest in the medical community (Farah, et al.,  Nat. Rev. Neuroscience  2004, 5, 421-425). Enhancement of learning and memory has been reported with amphetamines and derivatives thereof as well as other centrally-acting drugs. Certain nutritional supplements have also been reported to improve mental functions such as cognition and memory (Lanni, C., et al.,  Pharmacol. Res.  2004, 57, 196-213). However, many of these suffer from limited efficacy and/or untoward side effects due to their mechanisms of action. 
     Histone Acetyltransferases (HATs) are involved in histone acetylation (leading to gene activation), chromosome decondensation, DNA repair and non-histone substrate modification. 
     SUMMARY OF THE INVENTION 
     In one aspect, the invention is directed to methods and compositions for enhancing memory and learning in subjects. 
     In one aspect, the invention is directed to methods for increasing histone acetylation in a subject. 
     In one aspect, the invention is directed to methods for improving memory retention in a subject. 
     In one aspect, the invention is directed to methods for treating memory loss or a learning disability in a subject 
     In some embodiments, the methods and compositions that are useful for treating, suppressing and/or preventing afflictions related to memory loss or learning disabilities in subjects. 
     In some embodiments, the methods comprise administering to the subject a therapeutically effective amount of compound (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, or a composition comprising compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     In some embodiments, the methods and compositions are useful for enhancing memory and/or learning in subjects. In some embodiments, the methods and compositions are useful for treating, suppressing and/or preventing afflictions related to memory loss or learning disabilities in subjects. 
     In some embodiments, the subject is not afflicted with a neurodegenerative disease. In some embodiments, the neurodegenerative disease comprises Adrenoleukodystrophy (ALD), Alcoholism, Alexander&#39;s disease, Alper&#39;s disease, Alzheimer&#39;s disease, Amyotrophic lateral sclerosis (Lou Gehrig&#39;s Disease), Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Familial fatal insomnia, Frontotemporal lobar degeneration, Huntington&#39;s disease, HIV-associated dementia, Kennedy&#39;s disease, Krabbe&#39;s disease, Lewy body dementia, Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy, Niemann Pick disease, Parkinson&#39;s disease, Pelizaeus-Merzbacher Disease, Pick&#39;s disease, Primary lateral sclerosis, Prion diseasesm Progressive Supranuclear Palsy, Rett&#39;s syndrome, Tau-positive FrontoTemporal dementia, Tau-negative FrontoTemporal dementia, Refsum&#39;s disease, Sandhoff disease, Schilder&#39;s disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten disease (also known as Batten disease), Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, or Toxic encephalopathy. 
     In some embodiments, the present invention provides a method for enhancing memory in normal subjects. In some embodiments, the present invention provides for a method of improving learning in subjects. In some embodiments, the subject does not suffer from a neurodegenerative condition or disease. 
     In some embodiments, compound (I) increases histone acetylation. In some embodiments, histone acetylation comprises acetylation of histones H2B, H3, H4, or a combination thereof. In some embodiments, histone acetylation comprises acetylation of histone lysine residues H3K4, H3K9, H3K14, H4K5, H4K8, H4K12, H4K16, or a combination thereof. 
     In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, monkey, guinea pig, dog, or human. In some embodiments, the subject is a mouse, rat, monkey or human. In some embodiments, the subject is a mouse or a human. In some embodiments, the subject is a human. 
     In some embodiments, the methods reduce pain, anxiety or fear. In some embodiments, the methods reduce anxiety or fear. In some embodiments, the methods reduce anxiety. In some embodiments, the methods increase neurotransmission. 
     These and other embodiments of the invention are further described in the following sections of the application, including the Detailed Description, Examples, and Claims. Still other objects and advantages of the invention will become apparent by those of skill in the art from the disclosure herein, which are simply illustrative and not restrictive. Thus, other embodiments will be recognized by the ordinarily skilled artisan without departing from the spirit and scope of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  is a photograph of a western blot showing acetylation levels of H3 in the cortex and hippocampus. Mice were administered with MOM via cannula (100 μg/μl per side) or mice were administered YF2 (Compound 1) (50 mg/kg, i.p.). 
         FIG. 2  is a photograph of a western blot showing acetylation levels of H3 in the hippocampus. Mice were administered with YF2 (Compound 1) (i.p. dissolved in saline) at 5 mg/kg, 10 mg/kg, or 20 mg/kg. 
         FIG. 3  is a graph showing the effect of OA2 (Compound 1) on HDAC1 activity. 
         FIG. 4  is a graph showing the effect of OA2 (Compound 1) on HDAC3/NCOR2 activity. 
         FIG. 5  is a graph showing the effect of OA2 (Compound 1) on HDAC5FL activity. 
         FIG. 6  is a graph showing the effect of OA2 (Compound 1) on HDAC7 activity. 
         FIG. 7  is a graph showing the effect of OA2 (Compound 1) on HDAC8 activity. 
         FIG. 8  is a graph showing the effect of OA2 (Compound 1) on HDAC10 activity. 
         FIG. 9  is a graph showing the effect of OA2 (Compound 1) on HDAC11 activity. 
         FIG. 10  is a graph showing the effect of OA2 (Compound 1) on Sirtuin1 activity. 
         FIG. 11  is a graph showing the effect of OA2 (Compound 1) on Sirtuin2 activity. 
         FIG. 12  is a graph showing the effect of OA2 (Compound 1) on HDAC6 activity. 
         FIG. 13  is a graph showing the effect of the HDAC inhibitor, SAHA, on HDAC1 activity. 
         FIG. 14  is a graph showing the effect of the HDAC inhibitor, SAHA, on HDAC3/NCOR2 activity. 
         FIG. 15  is a graph showing the effect of the HDAC inhibitor, SAHA, on HDAC6 activity. 
         FIG. 16  shows dose-response curves for human CBP, p300, PCAF and GCN5 activation by different concentrations of Compound 1. Calculated Compound 1 EC 50  values for CBP, p300, PCAF and GCN5 are: 0.82 μM, 0.79 μM, 18.11 μM and 65.19 μM are respectively. 
         FIG. 17  is a graph showing pharmacokinetic properties of Compound 1. The amount of Compound 1 in the brain is higher than that in the plasma. Compound 1 is rapidly absorbed in the brain (see Table 14). The elimination half-lives of Compound 1 in the brain and plasma are ˜40 min i.p. and 60 min. p.o. The distribution of Compound 1 to the brain is fast. Compound 1 does not induce any adverse effects up to 300 mg/kg (i.p.) in acute toxicity experiments. Chronic administration (45 days, i.p., daily, 20 mg/kg) of Compound 1 did not have adverse effects. 
         FIG. 18  is a bar graph demonstrating contextual fear conditioning responses after administration of Compound 1 (1, 5, and 20 mg/kg) to wild-type mice. 
         FIG. 19  is a bar graph demonstrating the assessment of sensory threshold in mice treated with vehicle or YF2 (Compound 1) (5 mg/kg). 
         FIG. 20  is a graph showing the kinetics of the HAT agonist, Compound 1, in the blood. Compound 1 was administered (20 mg/kg. i.p.) to mice and then blood was sampled from tails at different time points. 
         FIG. 21  is photograph of a western blot that shows histone 3 acetylation levels of mice hippocampus. 
         FIG. 22  shows that an acute administration of YF2 (Compound 1) increased specific acetylation of H3, H4, and H2B in hippocampal lysates. n=3 and p&lt;0.05 per group. 
         FIG. 23  shows beneficial effect of YF2 (Compound 1) on Ab42-induced reduction in BDNF levels. YF2 rescued Aβ-induced decrease in hippocampal BDNF levels (n=3 per each group, p&lt;0.05). Aβ was infused through cannulas. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Memory is known to be modulated by epigenetics through regulation of gene expression. Epigenetics is defined as the mechanism that changes gene expression by ‘marking’ DNA or its associated proteins, through processes such as DNA methylation and histone (H) modification, without changing the DNA sequence itself (Rakyan, V. K., et al.,  Biochem J.,  2001. 356(Pt 1): p. 1-10; herein incorporated by reference in its entirety). Modification of histones by, for example, the addition or removal of acetyl or methyl functional groups causes the chromatin structure to open or close, so that the information contained within the DNA is made more or less accessible to transcription factors. Hence, deregulation of one of the epigenetic mechanisms might lead to memory disruption. For instance, reduction of histone acetylation causes the chromatin structure to close, so that the information contained within the DNA might be less accessible to transcription factors and memory formation (Rakyan, V. K., et al.,  Biochem J.,  2001. 356(Pt 1):1-10; herein incorporated by reference in its entirety). 
     The main strategy that is currently used to up-regulate histone acetylation involves inhibition of histone deacetylases (HDACs), enzymes that remove an acetyl group from histones. However, the pleiotropic effect of nonspecific HDAC inhibition may hamper the therapeutic potential of HDAC inhibitors ( J. Virol.  2001. 75(4): 1909-17;  J. Virol.  2003. 77(21): 11425-35; Knutson, S. K.,  Biochemistry.  2008, Vanderbilt: Nashville.167; PLoS One, 2009. 4(8): p. e6612; each herein incorporated by reference in its entirety). 
     HATs share a highly conserved motif containing an acetyl-CoA binding site. Specific HAT activators are potential tools for pharmacological research and might find therapeutic applications. HAT activators have been reported; however these compounds are poorly soluble and poorly membrane permeant, and thus not considered acceptable drug candidates for the treatment of diseases and other afflictions. For example, N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide is very poorly solubile in water and precipitated as soon as it was put in H 2 O ( J. Phys Chem B,  2007. 111(17): 4527-34). 
     In one aspect, the invention is directed to methods and compositions for enhancing memory and learning in subjects. 
     In one aspect, the invention is directed to methods for increasing histone acetylation in a subject. 
     In one aspect, the invention is directed to methods for improving memory retention in a subject. 
     In one aspect, the invention is directed to methods for treating memory loss or a learning disability in a subject 
     In some embodiments, the methods and compositions that are useful for treating, suppressing and/or preventing afflictions related to memory loss or learning disabilities in subjects. 
     In some embodiments, the methods comprise administering to the subject a therapeutically effective amount of compound (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, or a composition comprising compound (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     In some embodiments, the subject is not afflicted with a neurodegenerative disease. In one embodiment, the neurodegenerative disease comprises Adrenoleukodystrophy (ALD), Alcoholism, Alexander&#39;s disease, Alper&#39;s disease, Alzheimer&#39;s disease, Amyotrophic lateral sclerosis (Lou Gehrig&#39;s Disease), Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Familial fatal insomnia, Frontotemporal lobar degeneration, Huntington&#39;s disease, HIV-associated dementia, Kennedy&#39;s disease, Krabbe&#39;s disease, Lewy body dementia, Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy, Niemann Pick disease, Parkinson&#39;s disease, Pelizaeus-Merzbacher Disease, Pick&#39;s disease, Primary lateral sclerosis, Prion diseasesm Progressive Supranuclear Palsy, Rett&#39;s syndrome, Tau-positive FrontoTemporal dementia, Tau-negative FrontoTemporal dementia, Refsum&#39;s disease, Sandhoff disease, Schilder&#39;s disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten disease (also known as Batten disease), Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, or Toxic encephalopathy. 
     In some embodiments, the present invention provides a method for enhancing memory in normal subjects. In some embodiments, the present invention provides for a method of improving learning in subjects. In some embodiments, the subject suffers from age-related memory impairment. In some embodiments, the subject does not suffer from a neurodegenerative condition. In some embodiments, the subject does not suffer from Alzheimer&#39;s Disease. 
     In some embodiments, the invention provides for memory enhancement in normal subjects. In some embodiments, the invention provides for memory enhancement and/or learning improvement in cognitively deficient subjects. 
     In some embodiments, the invention provides for memory enhancement in aging subjects. In some embodiments, the subject is greater than about 40 years old. In some embodiments, the subject is greater than about 45 years old, greater than about 50 years old, greater than about 55 years old, greater than about 60 years old, or greater than about 65 years old. 
     In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, monkey, guinea pig, dog, or human. In some embodiments, the subject is a mouse, rat, monkey or human. In some embodiments, the subject is a mouse or a human. In some embodiments, the subject is a human. 
     In some embodiments, the methods reduce pain, anxiety or fear. In some embodiments, the methods reduce anxiety or fear. In some embodiments, the methods reduce anxiety. In some embodiments, the methods increase neurotransmission. 
     In some embodiments, the invention provides for methods of treatment using compound I, which has histone acetyltransferase activity, HAT activation potency, high selectivity, reasonable pharmacokinetics and good permeability across the blood-brain-barrier (BBB). 
     In some embodiments, the methods increase gene expression in a subject resulting in enhanced memory and cognition. 
     Abbreviations and Definitions 
     The term “compound (I)” or “compound 1” as used herein means the compound designated as formula I or 1. It is also referred to herein as “YF2” or “OA2”. 
     The term “composition(s) of the invention” as used herein means compositions comprising compound (I) or pharmaceutically acceptable salts thereof. The compositions of the invention may further comprise other agents such as, for example, excipients, stabilants, lubricants, solvents, and the like. 
     The term “method(s) of the invention” as used herein means methods comprising treatment with the compound (I) and/or compositions of the invention. 
     A “pharmaceutical composition” refers to a mixture of compound (I) described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. 
     The term “pharmaceutically acceptable salt” is intended to include salts derived from inorganic or organic acids including, for example hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluroacetic, trichloroacetic, naphthalene-2 sulfonic and other acids; and salts derived from inorganic or organic bases including, for example sodium, potassium, calcium, ammonium or tetrafluoroborate. Exemplary pharmaceutically acceptable salts are found, for example, in Berge, et al. ( J. Pharm. Sci.  1977, 66(1), 1 and Gould, P.,  Int. J. Pharmaceutics  1986, 33, 201-217; each herein incorporated by reference in its entirety). Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2:1. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate. 
     The term “acid” contemplates all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuric acids, phosphoric acids and nitric acids. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, and fatty acids. Preferred acids are straight chain or branched, saturated or unsaturated C1-C20 aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C6-C12 aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha-hydroxy acids, such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tataric acid and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid and lactobionic acid. 
     As used herein the term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower). 
     An “effective amount”, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration of the memory loss or cognition, or one or more symptoms thereof, prevent the advancement of conditions related to memory loss or cognition, improve cognition, learning or memory in subjects not afflicted with a neurodegenerative disorder, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects. 
     As used herein and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease, a stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. 
     The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in “Remington&#39;s Pharmaceutical Sciences” by E.W. Martin (hereby incorporated by reference in its entirety). 
     The terms “animal,” “subject” and “patient” as used herein include all members of the animal kingdom including, but not limited to, mammals (e.g., mice, rats, cats, monkeys, dogs, horses, swine, etc.) and humans. 
     Acetylation and Methylation of DNA and Histones 
     Histone deacetylase (HDAC) and histone acetyltransferase (HAT) are enzymes that influence transcription by selectively deacetylating or acetylating the ε-amino groups of lysine located near the amino termini of core histone proteins. Chromatin acetylation correlates with transcriptional activity (euchromatin), whereas deacetylation correlates with gene silencing. Interestingly, it was shown that increased acetylation of H3 in area CA1 of the hippocampus (an area in the brain that plays an important role in long-term memory) occurs following associative memory. Additionally, by inhibiting HDAC, they were able to manipulate changes in the chromatin and enhance the formation of long-term memory. 
     The DNA is firstly wrapped around an octamer complex of histones (H) to form nucleosomal units, giving the appearance of beads on a string ( Nature,  2001. 409(6822): 860-921; herein incorporated by reference in its entirety). In turn, these nucleosomal units, fold into a higher-order chromatin fiber ( Cell,  1999. 98(3): 285-94; herein incorporated by reference in its entirety). Each histone-octamer complex contains two copies of histones H3 and H4 bordered by two copies of histones 2A and 2B. Histone H1 and its avian variant H5 are linker histones that bind the nucleosome and both the entry and exit sites of the DNA, thus locking the DNA into place and allowing the formation of higher order structure. Every histone has a globular domain, which mediates histone-histone interactions, and an N-terminal ‘tail’ extension. The histone cores and in particular their tails, are targets for a considerable number of covalent modifications, such as acetylation, ubiquitination, sumoylation, phosphorylation, citrullination, ADP-ribosylation, and methylation ( Angew Chem Int Ed Engl,  2005. 44(21): 3186-216; herein incorporated by reference in its entirety). Histone modifications associated with active gene transcription, such as H3 Lys4 methylation and H3 Lys56 acetylation, were found to lead to gene expression. On the other hand, histone modifications associated with the inactivation of gene transcription, such as H3 Lys27 methylation and H2A Lys119 ubiquitination were found to cause gene silencing. Of particular interest for this application are histone 2B, 3 and 4 because they have been shown to be involved in memory processes ( Nature,  2007. 447(7141): 178-82;  Neuron,  2004. 42(6): 947-59; each herein incorporated by reference in its entirety). Studies of aging-associated memory dysfunction are discussed in  Science  2010, 328, 701; herein incorporated by reference in its entirety. 
     HATs and HDACs. Histone modifications and their combinations have been proposed to be involved in gene regulation by modifying the chromatin accessibility and by acting as docking sites for transcription factors and modifying enzymes ( Bioessays,  2005. 27(2): 164-75;  Nature,  2000. 403(6765): 41-5; herein incorporated by reference in its entirety). One of the most studied histone modifications is the acetylation of the evolutionary-conserved lysine residues on the histone N-termini by histone acetyltransferase (HAT). In contrast, histone deacetylation, catalyzed by histone deacetylase (HDAC), was found to package the DNA into a more condensed form, limiting the access of transcription factors and thus acting as a gene silencer ( Trends Biochem Sci,  2000. 25(3): 121-6; herein incorporated by reference in its entirety). The HATs involved in the regulation of gene expression include at least three groups of enzymes ( J. Biochem,  2005. 138(6): 647-62; herein incorporated by reference in its entirety). The general control non-derepressible 5 (Gcn5) is the founding member of the Gcn5 N-acetyltransferases (GNATs). The GNAT family members include Gcn5, PCAF, Elp3, HAT1m Hpa2 and Nut1. The MYST family is named after the founding members of the family:  M orf,  Y bf2,  S as2 and  T ip60. In addition, other proteins including CBP/p300, Taf1 and a number of nuclear receptor co-activators have been shown to possess intrinsic HAT activity. However, these proteins do not contain a consensus domain and therefore represent an ‘orphan class’ of HAT enzymes. 
     HDACs form repressor complexes with transcription activators and with other HDACs ( Biochem J,  2003. 370(Pt 3): 737-49; herein incorporated by reference in its entirety). Mammalian HDACs can be divided into the classical and the silent information regulator 2 (Sir2)-related protein (sirtruin) families ( Oncogene,  2007. 26(37): 5310-8; herein incorporated by reference in its entirety). In humans, members of the classical family have another subdivision, which include class I, II and IV, that share sequence similarity and require Zn+ for deacetylase activity. Class I HDACs (HDAC1-3, HDAC8) are related to the yeast gene repressor Rpd3p, and are subunits of at least two distinct co-repressor complexes, the Sin3 complex and the NuRD complex. Class II HDACs (HDAC4-7, 9 and 10) are similar to the yeast Hdalp HDAC, they act as gene repressors and have been implicated in various roles in cell differentiation and development. Class IV comprises HDAC11, which has some features of both class I and II HDACs. The sirtruin family includes class III HDACs (SIRT1-7), which are similar to yeast Sir2. Class III HDACs are biochemically and structurally distinct from the classical family and require NAD +  as a cofactor. HDACs appear to be involved in gene silencing and heterochromatin formation at centromeres and telomeres (for a review see ( J Mol Biol,  2004. 338(1):17-31; herein incorporated by reference in its entirety). 
     Alterations in epigenetic modifications including acetylation and methylation of DNA and histones may contribute to gene expression changes in cancer and neurological diseases. Addition of acetyl group on histones by Histone Acetyltransferases (HATs) enhances gene expression, while its removal by Histone Deacytylases (HDAC) reduces gene expression. Reduction in histone acetylation has been found in a variety of ailments such as tumors, mood disorders, and neurodegenerative diseases. Examples of HATs include, but are not limited to GCN5, GCN5L, PCAF, HAT1, ELP3, HPA2, ESA1, SAS2, SAS3, TIP60, HBO1, MOZ, MORF, MOF, SRC1, SRC3, TIF2, GRIP1, ATF-2 [see Lee and Workman (2007) Nat Rev Mol Cell Biol., 8(4):284-95, Marmorstein (2001) J Molec Biol. 311: 433-444; and Kimura et al., (2005) J Biochem. 138(6): 647-662; each of which are hereby incorporated by reference in their entireties]. In some embodiments, the HAT activator compound is directed to GCN5, GCN5L, HAT1, PCAF, or a combination thereof. In some embodiments, the HAT activator compound is directed to proteins that possess intrinsic HAT activity, such as nuclear receptor co-activators (for example, CBP/p300 and Taf1). In some embodiments, the acetylation of H2, H3, and/or H4 histones is increased. 
     Increasing histone acetylation has been shown to improve outcome in a wide variety of diseases as diverse as asthma, infectious disease and psychiatric diseases. Although clinical trials of several HDAC inhibitors are currently underway, the alternative strategy where by histone acetylation is increased by HAT activation has not been extensively explored. For example, compounds in U.S. Patent Publication No. US2009076155 and PCT Publication No. WO2004053140 (each herein incorporated by reference in its entirety) have poor solubility and membrane permeability. Furthermore, the compounds disclosed in the patent applications do not disclose any data for the treatment of any diseases. Regulation of HAT is also discussed, for example, in U.S. Patent Publication No. US20040091967 and U.S. Pat. No. 7,750,047 (each herein incorporated by reference in its entirety). 
     No HAT activator is currently in drug trials, however several HDAC inhibitors are currently in clinical trials. Some of these HDAC inhibitors (HDACi) have shown therapeutic efficacy in preclinical trials. Without being bound by theory, it is believed that HAT activators may be useful drug candidates with a role similar to HDACi. However, previously available HAT activators had little solubility and membrane permeability, making them unsuitable as drugs. 
     Some HDACi are or were being developed for neurological diseases, such as an HDACi from Merck (Whitehouse Station, N.J.) that is being used for the treatment of neurodegenerative diseases; and HDACi from TopoTarget (Rockaway, N.J.) that was being used for the treatment of Huntington&#39;s disease, now discontinued; isovaleramide NPS-1776 (NPS Pharmaceutical, Bedminster, N.J.) that was being used for bipolar disorder, epilepsy, and migraines, now discontinued; and a histone acetyltransferase inhibitor for cancer from TopoTarget A/S (København, Denmark), which was discontinued in the preclinical stage. Histone Acylation is discussed in  Science  2010, 328, 753 and  Nature  2009, 459, 55; each herein incorporated by reference in its entirety. 
     Here, a HAT activator with improved solubility and membrane permeability is described and its potency in-vitro as well as in an animal model are shown. Compound (I) and other HAT activator compounds are also described in PCT/US10/59925, incorporated herein by reference in its entirety. In vitro and behavioral data show that HAT activator compound (I) can acetylate histone H3 in brain and ameliorate memory deficits in a mouse model of Alzheimer&#39;s disease. For example, compound (I) can be used as adjuvant therapy in several cancers, psychiatric and neurodegenerative diseases and may improve efficacy and safety of treatment for these disorders. Furthermore, the compound (I) exhibits good solubility and permeability of the Blood-Brain-Barrier (See Abel and Zukin (2008) Current Opinion in Pharmacology 8:57-64; and Lee and Workman (2007) Nat Rev Mol Cell Biol 8:284-295; each herein incorporated by reference in its entirety). 
     HAT1 is also known as KAT1 (K(lysine) acetyltransferase 1). The protein encoded by this gene is a type B histone acetyltransferase (HAT) that is involved in the rapid acetylation of newly synthesized cytoplasmic histones, which are in turn imported into the nucleus for de novo deposition onto nascent DNA chains. Histone acetylation, particularly of histone H4, plays an important role in replication-dependent chromatin assembly. 
     SEQ ID NO: 1 is the human wild type amino acid sequence corresponding to the HAT protein, the HAT1 enzyme (residues 1-419): 
     
       
         
           
               
               
               
            
               
                   1 
                 MAGFGAMEKF LVEYKSAVEK KLAEYKCNTN TAIELKLVRF PEDLENDIRT FFPEYTHQLF 
                   
               
               
                   
               
               
                  61 
                 GDDETAFGYK GLKILLYYIA GSLSTMFRVE YASKVDENFD CVEADDVEGK IRQIIPPGFC 
               
               
                   
               
               
                 121 
                 TNTNDFLSLL EKEVDFKPFG TLLHTYSVLS PTGGENFTFQ IYKADMTCRG FREYHERLQT 
               
               
                   
               
               
                 181 
                 FLMWFIETAS FIDVDDERWH YFLVFEKYNK DGATLFATVG YMTVYNYYVY PDKTRPRVSQ 
               
               
                   
               
               
                 241 
                 MLILTPFQGQ GHGAQLLETV HRYYTEFPTV LDITAEDPSK SYVKLRDFVL VKLCQDLPCF 
               
               
                   
               
               
                 301 
                 SREKLMQGFN EDMAIEAQQK FKINKQHARR VYEILRLLVT DMSDAEQYRS YRLDIKRRLI 
               
               
                   
               
               
                 361 
                 SPYKKKQRDL AKMRKCLRPE ELTNQMNQIE ISMQHEQLEE SFQELVEDYR RVIERLAQE 
               
            
           
         
       
     
     SEQ ID NO: 2 is the human wild type nucleotide sequence corresponding to HAT protein, the HAT1 enzyme (residues 1-1682), wherein the underscored ATG denotes the beginning of the open reading frame: 
     
       
         
           
               
               
               
            
               
                    1 
                 ctgtgcggtc acttccggcc cgggagcgcg cgggttgatt cgtccttcct cagccgcggg 
                   
               
               
                   
               
               
                   61 
                 tgatcgtagc tcggaa   atg   g cgggatttgg tgctatggag aaatttttgg tagaatataa 
               
               
                   
               
               
                  121 
                 gagtgcagtg gagaagaaac tggcagagta caaatgtaac accaacacag caattgaact 
               
               
                   
               
               
                  181 
                 aaaattagtt cgttttcctg aagatcttga aaatgacatt agaactttct ttcctgagta 
               
               
                   
               
               
                  241 
                 tacccatcaa ctctttgggg atgatgaaac tgcttttggt tacaagggtc taaagatcct 
               
               
                   
               
               
                  301 
                 gttatactat attgctggta gcctgtcaac aatgttccgt gttgaatatg catctaaagt 
               
               
                   
               
               
                  361 
                 tgatgagaac tttgactgtg tagaggcaga tgatgttgag ggcaaaatta gacaaatcat 
               
               
                   
               
               
                  421 
                 tccacctgga ttttgcacaa acacgaatga tttcctttct ttactggaaa aggaagttga 
               
               
                   
               
               
                  481 
                 tttcaagcca ttcggaacct tacttcatac ctactcagtt ctcagtccaa caggaggaga 
               
               
                   
               
               
                  541 
                 aaactttacc tttcagatat ataaggctga catgacatgt agaggctttc gagaatatca 
               
               
                   
               
               
                  601 
                 tgaaaggctt cagacctttt tgatgtggtt tattgaaact gctagcttta ttgacgtgga 
               
               
                   
               
               
                  661 
                 tgatgaaaga tggcactact ttctagtatt tgagaagtat aataaggatg gagctacgct 
               
               
                   
               
               
                  721 
                 ctttgcgacc gtaggctaca tgacagtcta taattactat gtgtacccag acaaaacccg 
               
               
                   
               
               
                  781 
                 gccacgtgta agtcagatgc tgattttgac tccatttcaa ggtcaaggcc atggtgctca 
               
               
                   
               
               
                  841 
                 acttcttgaa acagttcata gatactacac tgaatttcct acagttcttg atattacagc 
               
               
                   
               
               
                  901 
                 ggaagatcca tccaaaagct atgtgaaatt acgagacttt gtgcttgtga agctttgtca 
               
               
                   
               
               
                  961 
                 agatttgccc tgtttttccc gggaaaaatt aatgcaagga ttcaatgaag atatggcgat 
               
               
                   
               
               
                 1021 
                 agaggcacaa cagaagttca aaataaataa gcaacacgct agaagggttt atgaaattct 
               
               
                   
               
               
                 1081 
                 tcgactactg gtaactgaca tgagtgatgc cgaacaatac agaagctaca gactggatat 
               
               
                   
               
               
                 1141 
                 taaaagaaga ctaattagcc catataagaa aaagcagaga gatcttgcta agatgagaaa 
               
               
                   
               
               
                 1201 
                 atgtctcaga ccagaagaac tgacaaacca gatgaaccaa atagaaataa gcatgcaaca 
               
               
                   
               
               
                 1261 
                 tgaacagctg gaagagagtt ttcaggaact agtggaagat taccggcgtg ttattgaacg 
               
               
                   
               
               
                 1321 
                 acttgctcaa gagtaaagat tatactgctc tgtacaggaa gcttgcaaat tttctgtaca 
               
               
                   
               
               
                 1381 
                 atgtgctgtg aaaaatctga tgactttaat tttaaaatct tgtgacattt tgcttatact 
               
               
                   
               
               
                 1441 
                 aaaagttatc tatctttagt tgaatatttt cttttggaga gattgtatat tttaaaatac 
               
               
                   
               
               
                 1501 
                 tgtttagagt ttatgagcat atattgcatt taaagaaaga taaagcttct gaaatactac 
               
               
                   
               
               
                 1561 
                 tgcaattgct tcccttctta aacagtataa taaatgctta gttgtgatat gttaatgtgt 
               
               
                   
               
               
                 1621 
                 gatgatatga ttcttaaata cttacaataa acctcattct taaatactta aaaaaaaaaa 
               
               
                   
               
               
                 1681 
                 aa 
               
            
           
         
       
     
     The polypeptide sequence of a HAT protein, human PCAF, is depicted in SEQ ID NO: 3. The nucleotide sequence of human PCAF is shown in SEQ ID NO: 4. Sequence information related to PCAF is accessible in public databases by GenBank Accession numbers NM_003884 (for mRNA) and NP_003875 (for protein). PCAF is also known as KAT2B (K(lysine) acetyltransferase 2B). CBP and p300 are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun and the adenoviral oncoprotein E1A. The protein encoded by this gene associates with p300/CBP. It has in vitro and in vivo binding activity with CBP and p300, and competes with E1A for binding sites in p300/CBP. It has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that this protein plays a direct role in transcriptional regulation. 
     SEQ ID NO: 3 is the human wild type amino acid sequence corresponding to the HAT protein, the PCAF enzyme (residues 1-832): 
     
       
         
           
               
               
               
            
               
                   1 
                 MSEAGGAGPG GCGAGAGAGA GPGALPPQPA ALPPAPPQGS PCAAAAGGSG ACGPATAVAA 
                   
               
               
                   
               
               
                  61 
                 AGTAEGPGGG GSARIAVKKA QLRSAPRAKK LEKLGVYSAC KAEESCKCNG WKNPNPSPTP 
               
               
                   
               
               
                 121 
                 PRADLQQIIV SLTESCRSCS HALAAHVSHL ENVSEEEMNR LLGIVLDVEY LFTCVHKEED 
               
               
                   
               
               
                 181 
                 ADTKQVYFYL FKLLRKSILQ RGKPVVEGSL EKKPPFEKPS IEQGVNNFVQ YKFSHLPAKE 
               
               
                   
               
               
                 241 
                 RQTIVELAKM FLNRINYWHL EAPSQRRLRS PNDDISGYKE NYTRWLCYCN VPQFCDSLPR 
               
               
                   
               
               
                 301 
                 YETTQVFGRT LLRSVFTVMR RQLLEQARQE KDKLPLEKRT LILTHFPKFL SMLEEEVYSQ 
               
               
                   
               
               
                 361 
                 NSPIWDQDFL SASSRTSQLG IQTVINPPPV AGTISYNSTS SSLEQPNAGS SSPACKASSG 
               
               
                   
               
               
                 421 
                 LEANPGEKRK MTDSHVLEEA KKPRVMGDIP MELINEVMST ITDPAAMLGP ETNFLSAHSA 
               
               
                   
               
               
                 481 
                 RDEAARLEER RGVIEFHVVG NSLNQKPNKK ILMWLVGLQN VFSHQLPRMP KEYITRLVFD 
               
               
                   
               
               
                 541 
                 PKHKTLALIK DGRVIGGICF RMFPSQGFTE IVFCAVTSNE QVKGYGTHLM NHLKEYHIKH 
               
               
                   
               
               
                 601 
                 DILNFLTYAD EYAIGYFKKQ GFSKEIKIPK TKYVGYIKDY EGATLMGCEL NPRIPYTEFS 
               
               
                   
               
               
                 661 
                 VIIKKQKEII KKLIERKQAQ IRKVYPGLSC FKDGVRQIPI ESIPGIRETG WKPSGKEKSK 
               
               
                   
               
               
                 721 
                 EPRDPDQLYS TLKSILQQVK SHQSAWPFME PVKRTEAPGY YEVIRFPMDL KTMSERLKNR 
               
               
                   
               
               
                 781 
                 YYVSKKLFMA DLQRVFTNCK EYNPPESEYY KCANILEKFF FSKIKEAGLI DK 
               
            
           
         
       
     
     SEQ ID NO: 4 is the human wild type nucleotide sequence corresponding to HAT protein, the PCAF enzyme (residues 1-4824), wherein the underscored ATG denotes the beginning of the open reading frame: 
     
       
         
           
               
               
               
            
               
                    1 
                 gcggaaaaga ggccgtgggg ggcctcccag cgctggcaga caccgtgagg ctggcagccg 
                   
               
               
                   
               
               
                   61 
                 ccggcacgca cacctagtcc gcagtcccga ggaacatgtc cgcagccagg gcgcggagca 
               
               
                   
               
               
                  121 
                 gagtcccggg caggagaacc aagggagggc gtgtgctgtg gcggcggcgg cagcggcagc 
               
               
                   
               
               
                  181 
                 ggagccgcta gtcccctccc tcctggggga gcagctgccg ccgctgccgc cgccgccacc 
               
               
                   
               
               
                  241 
                 accatcagcg cgcggggccc ggccagagcg agccgggcga gcggcgcgct agggggaggg 
               
               
                   
               
               
                  301 
                 cgggggcggg gaggggggtg ggcgaagggg gcgggagggc gtggggggag ggtctcgctc 
               
               
                   
               
               
                  361 
                 tcccgactac cagagcccga gagggagacc ctggcggcgg cggcggcgcc tgacactcgg 
               
               
                   
               
               
                  421 
                 cgcctcctgc cgtgctccgg ggcggc   atg   t ccgaggctgg cggggccggg ccgggcggct 
               
               
                   
               
               
                  481 
                 gcggggcagg agccggggca ggggccgggc ccggggcgct gcccccgcag cctgcggcgc 
               
               
                   
               
               
                  541 
                 ttccgcccgc gcccccgcag ggctccccct gcgccgctgc cgccgggggc tcgggcgcct 
               
               
                   
               
               
                  601 
                 gcggtccggc gacggcagtg gctgcagcgg gcacggccga aggaccggga ggcggtggct 
               
               
                   
               
               
                  661 
                 cggcccgaat cgccgtgaag aaagcgcaac tacgctccgc tccgcgggcc aagaaactgg 
               
               
                   
               
               
                  721 
                 agaaactcgg agtgtactcc gcctgcaagg ccgaggagtc ttgtaaatgt aatggctgga 
               
               
                   
               
               
                  781 
                 aaaaccctaa cccctcaccc actcccccca gagccgacct gcagcaaata attgtcagtc 
               
               
                   
               
               
                  841 
                 taacagaatc ctgtcggagt tgtagccatg ccctagctgc tcatgtttcc cacctggaga 
               
               
                   
               
               
                  901 
                 atgtgtcaga ggaagaaatg aacagactcc tgggaatagt attggatgtg gaatatctct 
               
               
                   
               
               
                  961 
                 ttacctgtgt ccacaaggaa gaagatgcag ataccaaaca agtttatttc tatctattta 
               
               
                   
               
               
                 1021 
                 agctcttgag aaagtctatt ttacaaagag gaaaacctgt ggttgaaggc tctttggaaa 
               
               
                   
               
               
                 1081 
                 agaaaccccc atttgaaaaa cctagcattg aacagggtgt gaataacttt gtgcagtaca 
               
               
                   
               
               
                 1141 
                 aatttagtca cctgccagca aaagaaaggc aaacaatagt tgagttggca aaaatgttcc 
               
               
                   
               
               
                 1201 
                 taaaccgcat caactattgg catctggagg caccatctca acgaagactg cgatctccca 
               
               
                   
               
               
                 1261 
                 atgatgatat ttctggatac aaagagaact acacaaggtg gctgtgttac tgcaacgtgc 
               
               
                   
               
               
                 1321 
                 cacagttctg cgacagtcta cctcggtacg aaaccacaca ggtgtttggg agaacattgc 
               
               
                   
               
               
                 1381 
                 ttcgctcggt cttcactgtt atgaggcgac aactcctgga acaagcaaga caggaaaaag 
               
               
                   
               
               
                 1441 
                 ataaactgcc tcttgaaaaa cgaactctaa tcctcactca tttcccaaaa tttctgtcca 
               
               
                   
               
               
                 1501 
                 tgctagaaga agaagtatat agtcaaaact ctcccatctg ggatcaggat tttctctcag 
               
               
                   
               
               
                 1561 
                 cctcttccag aaccagccag ctaggcatcc aaacagttat caatccacct cctgtggctg 
               
               
                   
               
               
                 1621 
                 ggacaatttc atacaattca acctcatctt cccttgagca gccaaacgca gggagcagca 
               
               
                   
               
               
                 1681 
                 gtcctgcctg caaagcctct tctggacttg aggcaaaccc aggagaaaag aggaaaatga 
               
               
                   
               
               
                 1741 
                 ctgattctca tgttctggag gaggccaaga aaccccgagt tatgggggat attccgatgg 
               
               
                   
               
               
                 1801 
                 aattaatcaa cgaggttatg tctaccatca cggaccctgc agcaatgctt ggaccagaga 
               
               
                   
               
               
                 1861 
                 ccaattttct gtcagcacac tcggccaggg atgaggcggc aaggttggaa gagcgcaggg 
               
               
                   
               
               
                 1921 
                 gtgtaattga atttcacgtg gttggcaatt ccctcaacca gaaaccaaac aagaagatcc 
               
               
                   
               
               
                 1981 
                 tgatgtggct ggttggccta cagaacgttt tctcccacca gctgccccga atgccaaaag 
               
               
                   
               
               
                 2041 
                 aatacatcac acggctcgtc tttgacccga aacacaaaac ccttgcttta attaaagatg 
               
               
                   
               
               
                 2101 
                 gccgtgttat tggtggtatc tgtttccgta tgttcccatc tcaaggattc acagagattg 
               
               
                   
               
               
                 2161 
                 tcttctgtgc tgtaacctca aatgagcaag tcaagggcta tggaacacac ctgatgaatc 
               
               
                   
               
               
                 2221 
                 atttgaaaga atatcacata aagcatgaca tcctgaactt cctcacatat gcagatgaat 
               
               
                   
               
               
                 2281 
                 atgcaattgg atactttaag aaacagggtt tctccaaaga aattaaaata cctaaaacca 
               
               
                   
               
               
                 2341 
                 aatatgttgg ctatatcaag gattatgaag gagccacttt aatgggatgt gagctaaatc 
               
               
                   
               
               
                 2401 
                 cacggatccc gtacacagaa ttttctgtca tcattaaaaa gcagaaggag ataattaaaa 
               
               
                   
               
               
                 2461 
                 aactgattga aagaaaacag gcacaaattc gaaaagttta ccctggactt tcatgtttta 
               
               
                   
               
               
                 2521 
                 aagatggagt tcgacagatt cctatagaaa gcattcctgg aattagagag acaggctgga 
               
               
                   
               
               
                 2581 
                 aaccgagtgg aaaagagaaa agtaaagagc ccagagaccc tgaccagctt tacagcacgc 
               
               
                   
               
               
                 2641 
                 tcaagagcat cctccagcag gtgaagagcc atcaaagcgc ttggcccttc atggaacctg 
               
               
                   
               
               
                 2701 
                 tgaagagaac agaagctcca ggatattatg aagttataag gttccccatg gatctgaaaa 
               
               
                   
               
               
                 2761 
                 ccatgagtga acgcctcaag aataggtact acgtgtctaa gaaattattc atggcagact 
               
               
                   
               
               
                 2821 
                 tacagcgagt ctttaccaat tgcaaagagt acaacccccc tgagagtgaa tactacaaat 
               
               
                   
               
               
                 2881 
                 gtgccaatat cctggagaaa ttcttcttca gtaaaattaa ggaagctgga ttaattgaca 
               
               
                   
               
               
                 2941 
                 agtgattttt tttcccctct gcttcttaga aactcaccaa gcagtgtgcc taaagcaagg 
               
               
                   
               
               
                 3001 
                 tggtttagtt ttttacaaag aattggacat gatgtattga agagacttgt aaatgtaata 
               
               
                   
               
               
                 3061 
                 attagcactt ttgaaaaaac aaaaaacctc cttttagctt ttcagatatg tatttaaatt 
               
               
                   
               
               
                 3121 
                 gaagtcatag gacattttta ttttatggaa tagattttaa tctatttact actattaagg 
               
               
                   
               
               
                 3181 
                 taaattttct atggcatgtc cattagctat ttcatgatag atgattaggg gtttcctcaa 
               
               
                   
               
               
                 3241 
                 aacctgtgtg tgaggaaatt gcacacagta gcaaaatttg gggaaatcca taacattttc 
               
               
                   
               
               
                 3301 
                 agaccatgaa tgaatgtttc catttttttc taatggaatg tgagagttta cttttatttt 
               
               
                   
               
               
                 3361 
                 attctgaagg actttaagga agggatacat gattttaaaa aagcctgtaa gaggtgaaat 
               
               
                   
               
               
                 3421 
                 atgtgatgtt tgaagtctct ttatagactt tttatatata ttttttaaaa cactcatcta 
               
               
                   
               
               
                 3481 
                 gatgaggtgc tttgagcagt tctgaaaaat gcagttccag gaaagcaact gctttggttc 
               
               
                   
               
               
                 3541 
                 ctaaggaaga aattctaaat aatgcaaact tttaaaataa gcatctaggt ttttgataat 
               
               
                   
               
               
                 3601 
                 tctgtctact tacaacaaac ttgttagtac ataaccacta ttttaataat tattttctct 
               
               
                   
               
               
                 3661 
                 acacaaatgt gtaatatcat atttgacttt gcttatgcag gccataagtt ccaaaagata 
               
               
                   
               
               
                 3721 
                 atttccctgc ccacaaaggc ataaacttga aaacacatga gattgaatca acatgcttta 
               
               
                   
               
               
                 3781 
                 ataggaaaag atgtatggtc tatatatgta tcaatctggt gaatcctcgt tctaataaag 
               
               
                   
               
               
                 3841 
                 gttctttttc ttttctatga tacacacagc cacgctgata atatgcaaat gaacattttc 
               
               
                   
               
               
                 3901 
                 ctttatgtct ctccagataa tgtttattgt ctgaggtaaa ttaaattccc accagggttt 
               
               
                   
               
               
                 3961 
                 gctgtcagta ttttaacacc cacattagta tatgcgtcca gggtcataac cccctaaaat 
               
               
                   
               
               
                 4021 
                 ccatcatgca accttattaa tctgtcttgg gattccagtt tagtgcttgg atttatttcc 
               
               
                   
               
               
                 4081 
                 tgattacact acatagaaaa gtgagacatc tgccattccc aactctggga aaaccaacta 
               
               
                   
               
               
                 4141 
                 atatacaacc atataaatga aggccatctt gatggtctca acactaattt ttatgatgca 
               
               
                   
               
               
                 4201 
                 aatttataca ctgatttttg taaaggacaa agttttaaaa gcgtatttaa cttgatgttt 
               
               
                   
               
               
                 4261 
                 tctatcagca taaataaaat ggtcatgaat agtcattaaa aacagttgcc agtgataatc 
               
               
                   
               
               
                 4321 
                 tgcatgaagg aaaaagaacc ctgcaaatgg ctattgagtt ggaagtattg tttttgatat 
               
               
                   
               
               
                 4381 
                 gtaagagata ttcagaatgc tcacactgaa aatgcctcaa ctttttaaag tgtaagaaac 
               
               
                   
               
               
                 4441 
                 caccatgagt ggtgtctaga tttctaatga agaatcatga tacagtttgg attaagtatc 
               
               
                   
               
               
                 4501 
                 ttggactggt tttaaacagt gctttgtacc ggatctgctg aagcatctgt ccagctggta 
               
               
                   
               
               
                 4561 
                 tcctgtgaaa gtttgttatt ttctgagtag acattcttat agagtattgt ctttaaaatc 
               
               
                   
               
               
                 4621 
                 agattgtctc ttctatattg aaagcatttt tatgttttct aatttaaaaa ttaatatttt 
               
               
                   
               
               
                 4681 
                 cttatagata ttgtgcaata aagctgaagt agaatgtgtg gtttttgcaa atgctttaac 
               
               
                   
               
               
                 4741 
                 agctgataaa aattttacat ttgtaaaatt aatatattgt actggtacaa aatagtttta 
               
               
                   
               
               
                 4801 
                 aattatattt taaaaagctt ccaa 
               
            
           
         
       
     
     The polypeptide sequence of a HAT protein, human GCN5L, is depicted in SEQ ID NO: 5. The nucleotide sequence of human GCN5L is shown in SEQ ID NO: 6. Sequence information related to GCN5L is accessible in public databases by GenBank Accession numbers NM_021078 (for mRNA) and NP_066564.2 (for protein). GCN5L is also known as KAT2A (K(lysine) acetyltransferase 2A). KAT2A, or GCN5, is a histone acetyltransferase (HAT) that functions primarily as a transcriptional activator. It also functions as a repressor of NF-kappa-B by promoting ubiquitination of the NF-kappa-B subunit RELA in a HAT-independent manner (Mao et al., Genes Dev. 2009 Apr. 1; 23(7):849-61; each herein incorporated by reference in its entirety). 
     SEQ ID NO: 5 is the human wild type amino acid sequence corresponding to the HAT protein, the GCN5L enzyme (residues 1-837): 
     
       
         
           
               
               
               
            
               
                   1 
                 MAEPSQAPTP APAAQPRPLQ SPAPAPTPTP APSPASAPIP TPTPAPAPAP AAAPAGSTGT 
                   
               
               
                   
               
               
                  61 
                 GGPGVGSGGA GSGGDPARPG LSQQQRASQR KAQVRGLPRA KKLEKLGVFS ACKANETCKC 
               
               
                   
               
               
                 121 
                 NGWKNPKPPT APRMDLQQPA ANLSELCRSC EHPLADHVSH LENVSEDEIN RLLGMVVDVE 
               
               
                   
               
               
                 181 
                 NLFMSVHKEE DTDTKQVYFY LFKLLRKCIL QMTRPVVEGS LGSPPFEKPN IEQGVLNFVQ 
               
               
                   
               
               
                 241 
                 YKFSHLAPRE RQTMFELSKM FLLCLNYWKL ETPAQFRQRS QAEDVATYKV NYTRWLCYCH 
               
               
                   
               
               
                 301 
                 VPQSCDSLPR YETTHVFGRS LLRSIFTVTR RQLLEKFRVE KDKLVPEKRT LILTHFPKFL 
               
               
                   
               
               
                 361 
                 SMLEEEIYGA NSPIWESGFT MPPSEGTQLV PRPASVSAAV VPSTPIFSPS MGGGSNSSLS 
               
               
                   
               
               
                 421 
                 LDSAGAEPMP GEKRTLPENL TLEDAKRLRV MGDIPMELVN EVMLTITDPA AMLGPETSLL 
               
               
                   
               
               
                 481 
                 SANAARDETA RLEERRGIIE FHVIGNSLTP KANRRVLLWL VGLQNVFSHQ LPRMPKEYIA 
               
               
                   
               
               
                 541 
                 RLVFDPKHKT LALIKDGRVI GGICFRMFPT QGFTEIVFCA VTSNEQVKGY GTHLMNHLKE 
               
               
                   
               
               
                 601 
                 YHIKHNILYF LTYADEYAIG YFKKQGFSKD IKVPKSRYLG YIKDYEGATL MECELNPRIP 
               
               
                   
               
               
                 661 
                 YTELSHIIKK QKEIIKKLIE RKQAQIRKVY PGLSCFKEGV RQIPVESVPG IRETGWKPLG 
               
               
                   
               
               
                 721 
                 KEKGKELKDP DQLYTTLKNL LAQIKSHPSA WPFMEPVKKS EAPDYYEVIR FPIDLKTMTE 
               
               
                   
               
               
                 781 
                 RLRSRYYVTR KLFVADLQRV IANCREYNPP DSEYCRCASA LEKFFYFKLK EGGLIDK 
               
            
           
         
       
     
     SEQ ID NO: 6 is the human wild type nucleotide sequence corresponding to HAT protein, the GCN5L enzyme (residues 1-3127), wherein the underscored ATG denotes the beginning of the open reading frame: 
     
       
         
           
               
               
               
            
               
                    1 
                 ggttgcccat gcggccctag ggctgggagc gcggcgccgc tctccgctgc gggggaggcc 
                   
               
               
                   
               
               
                   61 
                     atg   gcggaac cttcccaggc cccgaccccg gccccggctg cgcagccccg gccccttcag 
               
               
                   
               
               
                  121 
                 tccccagccc ctgccccaac tccgactcct gcacccagcc cggcttcagc cccgattccg 
               
               
                   
               
               
                  181 
                 actcccaccc cggcaccagc ccctgcccca gctgcagccc cagccggcag cacagggact 
               
               
                   
               
               
                  241 
                 ggggggcccg gggtaggaag tgggggggcc gggagcgggg gggatccggc tcgacctggc 
               
               
                   
               
               
                  301 
                 ctgagccagc agcagcgcgc cagtcagagg aaggcgcaag tccgggggct gccgcgcgcc 
               
               
                   
               
               
                  361 
                 aagaagcttg agaagctagg ggtcttctcg gcttgcaagg ccaatgaaac ctgtaagtgt 
               
               
                   
               
               
                  421 
                 aatggctgga aaaaccccaa gccccccact gcaccccgca tggatctgca gcagccagct 
               
               
                   
               
               
                  481 
                 gccaacctga gtgagctgtg ccgcagttgt gagcacccct tggctgacca cgtatcccac 
               
               
                   
               
               
                  541 
                 ttggagaatg tgtcagagga tgagataaac cgactgctgg ggatggtggt ggatgtggag 
               
               
                   
               
               
                  601 
                 aatctcttca tgtctgttca caaggaagag gacacagaca ccaagcaggt ctatttctac 
               
               
                   
               
               
                  661 
                 ctcttcaagc tactgcggaa atgcatcctg cagatgaccc ggcctgtggt ggaggggtcc 
               
               
                   
               
               
                  721 
                 ctgggcagcc ctccatttga gaaacctaat attgagcagg gtgtgctgaa ctttgtgcag 
               
               
                   
               
               
                  781 
                 tacaagttta gtcacctggc tccccgggag cggcagacga tgttcgagct ctcaaagatg 
               
               
                   
               
               
                  841 
                 ttcttgctct gccttaacta ctggaagctt gagacacctg cccagtttcg gcagaggtct 
               
               
                   
               
               
                  901 
                 caggctgagg acgtggctac ctacaaggtc aattacacca gatggctctg ttactgccac 
               
               
                   
               
               
                  961 
                 gtgccccaga gctgtgatag cctcccccgc tacgaaacca ctcatgtctt tgggcgaagc 
               
               
                   
               
               
                 1021 
                 cttctccggt ccattttcac cgttacccgc cggcagctgc tggaaaagtt ccgagtggag 
               
               
                   
               
               
                 1081 
                 aaggacaaat tggtgcccga gaagaggacc ctcatcctca ctcacttccc caaattcctg 
               
               
                   
               
               
                 1141 
                 tccatgctgg aggaggagat ctatggggca aactctccaa tctgggagtc aggcttcacc 
               
               
                   
               
               
                 1201 
                 atgccaccct cagaggggac acagctggtt ccccggccag cttcagtcag tgcagcggtt 
               
               
                   
               
               
                 1261 
                 gttcccagca cccccatctt cagccccagc atgggtgggg gcagcaacag ctccctgagt 
               
               
                   
               
               
                 1321 
                 ctggattctg caggggccga gcctatgcca ggcgagaaga ggacgctccc agagaacctg 
               
               
                   
               
               
                 1381 
                 accctggagg atgccaagcg gctccgtgtg atgggtgaca tccccatgga gctggtcaat 
               
               
                   
               
               
                 1441 
                 gaggtcatgc tgaccatcac tgaccctgct gccatgctgg ggcctgagac gagcctgctt 
               
               
                   
               
               
                 1501 
                 tcggccaatg cggcccggga tgagacagcc cgcctggagg agcgccgcgg catcatcgag 
               
               
                   
               
               
                 1561 
                 ttccatgtca tcggcaactc actgacgccc aaggccaacc ggcgggtgtt gctgtggctc 
               
               
                   
               
               
                 1621 
                 gtggggctgc agaatgtctt ttcccaccag ctgccgcgca tgcctaagga gtatatcgcc 
               
               
                   
               
               
                 1681 
                 cgcctcgtct ttgacccgaa gcacaagact ctggccttga tcaaggatgg gcgggtcatc 
               
               
                   
               
               
                 1741 
                 ggtggcatct gcttccgcat gtttcccacc cagggcttca cggagattgt cttctgtgct 
               
               
                   
               
               
                 1801 
                 gtcacctcga atgagcaggt caagggttat gggacccacc tgatgaacca cctgaaggag 
               
               
                   
               
               
                 1861 
                 tatcacatca agcacaacat tctctacttc ctcacctacg ccgacgagta cgccatcggc 
               
               
                   
               
               
                 1921 
                 tacttcaaaa agcagggttt ctccaaggac atcaaggtgc ccaagagccg ctacctgggc 
               
               
                   
               
               
                 1981 
                 tacatcaagg actacgaggg agcgacgctg atggagtgtg agctgaatcc ccgcatcccc 
               
               
                   
               
               
                 2041 
                 tacacggagc tgtcccacat catcaagaag cagaaagaga tcatcaagaa gctgattgag 
               
               
                   
               
               
                 2101 
                 cgcaaacagg cccagatccg caaggtctac ccggggctca gctgcttcaa ggagggcgtg 
               
               
                   
               
               
                 2161 
                 aggcagatcc ctgtggagag cgttcctggc attcgagaga caggctggaa gccattgggg 
               
               
                   
               
               
                 2221 
                 aaggagaagg ggaaggagct gaaggacccc gaccagctct acacaaccct caaaaacctg 
               
               
                   
               
               
                 2281 
                 ctggcccaaa tcaagtctca ccccagtgcc tggcccttca tggagcctgt gaagaagtcg 
               
               
                   
               
               
                 2341 
                 gaggcccctg actactacga ggtcatccgc ttccccattg acctgaagac catgactgag 
               
               
                   
               
               
                 2401 
                 cggctgcgaa gccgctacta cgtgacccgg aagctctttg tggccgacct gcagcgggtc 
               
               
                   
               
               
                 2461 
                 atcgccaact gtcgcgagta caaccccccg gacagcgagt actgccgctg tgccagcgcc 
               
               
                   
               
               
                 2521 
                 ctggagaagt tcttctactt caagctcaag gagggaggcc tcattgacaa gtaggcccat 
               
               
                   
               
               
                 2581 
                 ctttgggccg cagccctgac ctggaatgtc tccacctcgg attctgatct gatccttagg 
               
               
                   
               
               
                 2641 
                 gggtgccctg gccccacgga cccgactcag cttgagacac tccagccaag ggtcctccgg 
               
               
                   
               
               
                 2701 
                 acccgatcct gcagctcttt ctggaccttc aggcaccccc aagcgtgcag ctctgtccca 
               
               
                   
               
               
                 2761 
                 gccttcactg tgtgtgagag gtctcctggg ttggggccca gcccctctag agtagctggt 
               
               
                   
               
               
                 2821 
                 ggccagggat gaaccttgcc cagccgtggt ggcccccagg cctggtcccc aagagctttg 
               
               
                   
               
               
                 2881 
                 gaggcttgga ttcctgggcc tggcccaggt ggctgtttcc ctgaggacca gaactgctca 
               
               
                   
               
               
                 2941 
                 ttttagcttg agtgatggct tcaggggttg gaagttcagc ccaaactgaa gggggccatg 
               
               
                   
               
               
                 3001 
                 ccttgtccag cactgttctg tcagtctccc ccaggggtgg ggggtatggg gaccattcat 
               
               
                   
               
               
                 3061 
                 tccctggcat taatccctta gagggaataa taaagctttt tatttctctg tgaaaaaaaa 
               
               
                   
               
               
                 3121 
                 aaaaaaa 
               
            
           
         
       
     
     Knowledge of the primary sequence of a molecule of interest, such as a HAT polypeptide, and the similarity of that sequence with other proteins of the same histone acetyltransferase family (such as the GNAT family, the MYST family or the GCN5 family [see Lee and Owrkman (2007)  Nat Rev Mol Cell Biol.,  8(4):284-95, Marmorstein (2001)  J Molec Biol.  311: 433-444; and Kimura et al., (2005)  J. Biochem.  138(6): 647-662; each herein incorporated by reference in its entirety]), can provide information as to the inhibitors or antagonists of the protein of interest. Identification and screening antagonists can be further facilitated by determining structural features of the protein, e.g., using X-ray crystallography, neutron diffraction, nuclear magnetic resonance spectrometry, and other techniques for structure determination. These techniques may provide for rational approaches to the design or identification of antagonists, in addition to protein agonists. 
     A HAT Activator compound can be a compound that increases the activity and/or expression of a HAT molecule (e.g., GCN5, GCN5L, PCAF, or HAT1) in vivo and/or in vitro. HAT Activator compounds can be compounds that exert their effect on the activity of a HAT protein via the expression, via post-translational modifications, or by other means. In some embodiments, a HAT Activator compound can increase HAT protein or mRNA expression, or acetyltransferase activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 99%, or 100%. 
     In some embodiments, the methods comprise administering to the subject an effective amount of a composition comprising compound (I). In some embodiments, the subject does not exhibit abnormally elevated amyloid beta plaques, elevated Tau protein levels, accumulations of alpha-synuclein, accumulations of lipofuscin, or accumulation of cleaved TARDBP (TDB-43) levels, or any combination thereof. In some embodiments, the subject is not afflicted with Alzheimer&#39;s disease, Lewy body dementia, inclusion body myositis, Huntington&#39;s Disease, Parkinson&#39;s Disease, or cerebral amyloid angiopathy. In some embodiments, the subject is not afflicted with cancer. 
     In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing compound (I), or a pharmaceutically acceptable salt thereof; and (iii) administering said compound in a therapeutically effective amount to a subject in need of such treatment. 
     In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising compound (I), or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to a subject in need of such treatment. 
     In some embodiments, the methods comprise administering to the subject an effective amount of compound (I), or a pharmaceutically acceptable salt thereof, or a composition comprising compound (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers are well-known to those skilled in the art, and include, for example, adjuvants, diluents, excipients, fillers, lubricants and vehicles. Often, the pharmaceutically acceptable carrier is chemically inert toward the active compounds and is non-toxic under the conditions of use. Examples of pharmaceutically acceptable carriers may include, for example, water or saline solution, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. 
     In one aspect, the invention is directed to the use of compound (I), or a pharmaceutically acceptable salt thereof, in preparation of a medicament for enhancing learning or memory in a subject. 
     In one aspect, the invention is directed to the use of compound (I), or a pharmaceutically acceptable salt thereof, in preparation of a medicament for increasing histone acetylation in a subject. 
     In one aspect, the invention is directed to the use of compound (I), or a pharmaceutically acceptable salt thereof, in preparation of a medicament for improving memory retention in a subject. 
     In one aspect, the invention is directed to the use of compound (I), or a pharmaceutically acceptable salt thereof, in preparation of a medicament for treating memory loss or a learning disability in a subject. 
     In some embodiments, compound (I) is formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. According to some embodiments, the present invention provides a pharmaceutical composition comprising compound (I) in admixture with a pharmaceutically acceptable diluent and/or carrier. The pharmaceutically-acceptable carrier is “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. The pharmaceutically-acceptable carriers employed herein may be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as absorption delaying agents, analgesics, antibacterials, antifungals, buffers, binders, coatings, disintegrants, diluents, dispersants, emulsifiers, excipients, extenders, glidants, solubilizers, solvents, stabilizers, suspending agents, tonicity agents, vehicles and viscosity-increasing agents. Pharmaceutical additives, such as antioxidants, aromatics, colorants, flavor-improving agents, preservatives, and sweeteners, may also be added. Examples of acceptable pharmaceutical carriers include carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. In some embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. 
     Surfactants such as, for example, detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of formula N + R′R″R″′R″″Y − , in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals and Y −  is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants which can be used, amine salts of formula N + R′R″R″′, in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants which can be used, non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine, 
     When administered to a subject, compound (I) and pharmaceutically acceptable carriers can be sterile. Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The present compositions, if desired, may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. 
     The pharmaceutical formulations of the present invention are prepared by methods well-known in the pharmaceutical arts. Optionally, one or more accessory ingredients (e.g., buffers, flavoring agents, surface active agents, and the like) also are added. The choice of carrier is determined by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice. 
     Additionally, the compound and/or compositions of the present invention are administered to a human or animal subject by known procedures including oral administration, intraperitoneal, parenteral (e.g., intravenous), intradermal, subcutaneous, intranasal, transdermal, topical, transmucosal, rectal, sublingual or buccal administration. In some embodiments, compound (I) or a composition comprising compound (I) is administered orally. In some embodiments, compound (I) or a composition comprising compound (I) is administered intraperitoneally. 
     For oral administration, a formulation of compound (I) or compositions thereof may be presented in dosage forms such as capsules, tablets, powders, granules, or as a suspension or solution. Capsule formulations may be gelatin, soft-gel or solid. Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which are known in the art. Examples of such include carbohydrates such as lactose or sucrose, dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffering agents, disintegrants, and colorants. Orally administered compositions may contain one or more optional agents such as, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation. 
     The compositions may further comprise one or more sterile diluents, such as water, saline solutions, fixed oils, polyalkylene glycols, polyoxyalkylene glycols, glycerine, or other solvents; antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid, citric acid or sodium bisulfite, chelating agents such as EDTA, buffers such as acetate, citrate, phosphate and the like, tonicity adjusters such as sodium chloride or dextrose, pH adjusters such as weak acids or bases, etc. 
     In some embodiments, the composition is in unit dose form such as a tablet, capsule or single-dose vial. Suitable unit doses, i.e., therapeutically effective amounts, may be determined during clinical trials designed appropriately for each of the conditions for which administration of a chosen compound is indicated and will, of course, vary depending on the desired clinical endpoint. 
     Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EM™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition is preferably sterile and should be fluid to the extent that easy syringability exists. It is preferably stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a pharmaceutically acceptable polyol like glycerol, propylene glycol, liquid polyetheylene glycol, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it can be useful to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. 
     Sterile injectable solutions can be prepared by incorporating compound (I) or a composition thereof in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile powders for the preparation of sterile injectable solutions, examples of useful preparation methods are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. 
     Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. 
     Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. 
     Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. 
     The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. 
     In accordance with the methods of the present invention, in some embodiments the compounds and/or compositions of the invention are administered to the subject in a therapeutically effective amount to enhance or increase memory or cognition in the subject. This amount is readily determined by the skilled artisan, based upon known procedures, including analysis of titration curves established in vivo and methods and assays disclosed herein. 
     The dosage administered can be a therapeutically effective amount of the composition sufficient to result in memory or cognitive enhancement, increasing learning, or reducing memory loss in a subject. 
     In some embodiments, the methods comprise administration of a therapeutically effective dosage of compound (I). In some embodiments, the therapeutically effective dosage is at least about 0.05 mg/kg body weight, at least about 0.1 mg/kg body weight, at least about 0.25 mg/kg body weight, at least about 0.3 mg/kg body weight, at least about 0.5 mg/kg body weight, at least about 0.75 mg/kg body weight, at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg body weight, at least about 50 mg/kg body weight, at least about 75 mg/kg body weight, at least about 100 mg/kg body weight, at least about 200 mg/kg body weight, at least about 250 mg/kg body weight, at least about 300 mg/kg body weight, at least about 350 mg/kg body weight, at least about 400 mg/kg body weight, at least about 450 mg/kg body weight, at least about 500 mg/kg body weight, at least about 550 mg/kg body weight, at least about 600 mg/kg body weight, at least about 650 mg/kg body weight, at least about 700 mg/kg body weight, at least about 750 mg/kg body weight, at least about 800 mg/kg body weight, at least about 900 mg/kg body weight, or at least about 1000 mg/kg body weight. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit. 
     In some embodiments, the methods comprise a single dosage or administration (e.g., as a single injection or deposition). Alternatively, the methods comprise administration once daily, twice daily, three times daily or four times daily to a subject in need thereof for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or longer. In some embodiments, the methods comprise chronic administration. In some embodiments, the methods comprise administration over the course of several years or decades. 
     The dosage administered can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and/or dosing regimens. 
     The precise dose to be employed in the compositions will also depend on the route of administration, and should be decided according to the judgment of the practitioner and each patient&#39;s circumstances. In some embodiments of the invention, suitable dose ranges for oral administration of compound (I) are generally about 5 mg/day to about 1000 mg/day. In some embodiments, the oral dose of compound (I) is about 5 mg/day to about 800 mg/day. In some embodiments, the oral dose of compound (I) is about 5 mg/day to about 500 mg/day. In some embodiments, the oral dose of compound (I) is about 5 mg/day to about 250 mg/day. In some embodiments, the oral dose of compound (I) is about 5 mg/day to about 100 mg/day. In some embodiments, the oral dose of compound (I) is about 5 mg/day to about 50 mg/day. In some embodiments, the oral dose of compound (I) is about 5 mg/day. In some embodiments, the oral dose of compound (I) is about 10 mg/day. In some embodiments, the oral dose of compound (I) is about 20 mg/day. In some embodiments, the oral dose of compound (I) is about 50 mg/day. In some embodiments, the oral dose of compound (I) is about 100 mg/day. In some embodiments, the oral dose of compound (I) is about 250 mg/day. In some embodiments, the oral dose of compound (I) is about 500 mg/day. In some embodiments, the oral dose of compound (I) is about 750 mg/day. In some embodiments, the oral dose of compound (I) is about 1000 mg/day. 
     In some embodiments of the invention, suitable dose ranges for i.p. administration of compound (I) are generally about 5 mg/day to about 1000 mg/day. In some embodiments, the i.p. dose of compound (I) is about 5 mg/day to about 800 mg/day. In some embodiments, the i.p. dose of compound (I) is about 5 mg/day to about 500 mg/day. In some embodiments, the i.p. dose of compound (I) is about 5 mg/day to about 250 mg/day. In some embodiments, the i.p. dose of compound (I) is about 5 mg/day to about 100 mg/day. In some embodiments, the i.p. dose of compound (I) is about 5 mg/day to about 50 mg/day. In some embodiments, the i.p. dose of compound (I) is about 5 mg/day. In some embodiments, the i.p. dose of compound (I) is about 10 mg/day. In some embodiments, the i.p. dose of compound (I) is about 20 mg/day. In some embodiments, the i.p. dose of compound (I) is about 50 mg/day. In some embodiments, the i.p. dose of compound (I) is about 100 mg/day. In some embodiments, the i.p. dose of compound (I) is about 250 mg/day. In some embodiments, the i.p. dose of compound (I) is about 500 mg/day. In some embodiments, the i.p. dose of compound (I) is about 750 mg/day. In some embodiments, the i.p. dose of compound (I) is about 1000 mg/day. 
     Any of the therapeutic applications described herein can be applied to any subject in need of such therapy, including, for example, a mammal such as a mouse, rat, dog, a cat, a cow, a horse, a rabbit, a monkey, a pig, a sheep, a goat, or a human. 
     It will recognized that one or more features of any embodiments disclosed herein may be combined and/or rearranged within the scope of the invention to produce further embodiments that are also within the scope of the invention. 
     Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be within the scope of the present invention. 
     The invention is further described by the following non-limiting Examples. 
     EXAMPLES 
     Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. 
     Example 1 
     Synthesis of Compound 1 
     
       
         
         
             
             
         
       
     
     HAT Activator compound, compound 1 (I) was prepared according to Scheme 1. A solution of commercially available ethyl 6-ethoxy-2-hydroxybenzoate (2.10 g, 10.0 mmol) in EtOH and NaOH 1N (10 mL, 1:1) was heated to reflux for 2 h. The solution was acidified by adding HCl 1N and the resulting precipitate was diluted with CH 2 Cl 2  (50 mL) and washed with HCl 1N (3×50 mL). The organic layer was dried under Na 2 SO 4 , filtered and evaporated under reduced pressure. A white solid was obtained as the desired product 3(1.65 g, 91%). 
     EDC (2.19 mL, 12.35 mmol) was added dropwise to a solution of 3 (1.5 g, 8.23 mmol) and 3-chloro-4-(trifluoromethyl)aniline (1.61 g, 8.23 mmol) in CH 2 Cl 2  (15 mL) at 0° C. The reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the final product 4 (2.42 g, 82%) was isolated by precipitation from MeOH as a white needle-like solid. 
     To a solution of 4 (170 mg, 0.47 mmol), 2-(dimethylamino)ethanol (54 mg, 0.6 mmol), and PPh 3  (157 mg, 0.6 mmol) in THF (5 mL) DIAD (121 mg, 0.6 mmol) was added dropwise. The reaction was stirred for 24 h at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in AcOEt (30 mL). The organic layer was washed with water (3×30 mL), dried under Na 2 SO 4 , filtered, and concentrated to give a yellow oil, which was purified by flash chromatography (AcOEt:MeOH 9:1) affording compound 1 (135 mg, 70%) as a colorless oil.  1 H NMR (CDCl 3 , 300 MHz) δ 8.65 (s, 1H), 7.98 (d, 1H, J=7.8 Hz), 7.79 (d, 1H, J=1.5 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.29 (t, 1H, J=8.4 Hz), 6.60 (dd, 2H, J 1 =1.8, J 2 =8.4 Hz), 4.20 (t, 2H, J=5.1 Hz), 4.10 (q, 2H, J=6.9 Hz), 2.65 (t, 2H, J=5.4 Hz), 2.25 (s, 6H), 1.40 (t, 3H, J=7.2 Hz); Ms ESI (m/z) 431 (M+1) + . Compound 1 was treated with HCl 2M solution in ethyl ether and the white salt of 1 was collected by filtration. 
     Example 2 
     HAT Activator Compound Characteristics 
     The preparation of compound 1 was without a column and 2 phases were visible: clear and oily. Compound 1 (50 mg/kg, i.p.) was subsequently administered to mice. The des-ethoxy analog of compound 1, MOM, was also administered via cannula (100 μg/μL per side). Two and four hrs after its administration, the mice were sacrificed and hippocampi were extracted. Interestingly, while MOM did not cross the BBB, YF2 (compound 1) was able to cross the BBB, penetrate the cells and increase AcH3 (lane 1 vs. lanes 9, 10) ( FIG. 1 ). Given that the compound was not 100% clean and needed to be further purified/verified, more compound 1 was synthesized and purified. Purity was verified through Nuclear Magnetic Resonance (NMR) spectroscopy. Mice were administered with compound 1 (i.p. dissolved in saline) at 5, 10, 20 mg/Kg. Hippocampus extraction was made at 3 different time points (0.5, 1 and 2 hrs post treatment). A western blotting for AcH3 was then performed. Except for the 1 hr-10 mg/kg administration of YF2, YF2 dramatically increased AcH3 levels ( FIG. 2 ), indicating that YF2 (compound 1) crosses the BBB and the cell membrane. 
     Example 3 
     Compound 1 Increases Histone Acetylation by HAT Activation, Not HDAC Inhibition 
     HDAC inhibition causes an increase in histone acetylation. The inventors examined whether histone acetylation occurred via HDAC inhibition. The summary of the results is depicted in Table 1. The mean IC 50  values of the compounds (compound 1 and SAHA) are summarized in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Inhibitory Effects of the Compounds on HDAC Activities 
               
            
           
           
               
               
               
            
               
                   
                 IC 50  (nM) or % Inhibition 
                   
               
            
           
           
               
               
               
               
            
               
                   
                 HDACs 
                 1 
                 SAHA 
               
               
                   
                   
               
               
                   
                 HDAC1 
                 &gt;200 μM 
                 31 
               
               
                   
                 HDAC3/NCOR2 
                 &gt;200 μM 
                 38 
               
               
                   
                 HDAC5FL 
                 &gt;200 μM 
                 &gt;10 μM 
               
               
                   
                 HDAC6 
                 &gt;200 μM 
                 30 
               
               
                   
                 HADC7 
                 &gt;200 μM 
                 &gt;10 μM 
               
               
                   
                 HDAC8 
                 &gt;200 μM 
                 2,236   
               
               
                   
                 HDAC10 
                 &gt;200 μM 
                 65 
               
               
                   
                 HDAC11 
                 &gt;200 μM 
                 &gt;10 μM 
               
               
                   
                 Sirtuin 1 
                 &gt;200 μM 
                 &gt;10 μM 
               
               
                   
                 Sirtuin 2 
                 &gt;200 μM 
                 &gt;10 μM 
               
               
                   
                   
               
            
           
         
       
     
     The experiments were done blind, and the studies show that compound 1 has no HDAC inhibition properties. Compound 1 does not inhibit HDACs. 
     Materials and Methods 
     Materials: 
     HDAC Assay Buffer (BPS catalog number 50031) 
     HDAC Assay Developer (BPS catalog number 50030) 
     HDAC Substrate 1 (BPS number 50032) 
     HDAC Substrate 3 (BPS number 50037) 
     HDAC Class 2a Substrate 1 (BPS number 50040) 
     SAHA (Cayman Chemical, Ann Arbor, Mich., Catalog number 10009929) 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Compounds used in the studies 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 Dis- 
                   
                 Inter- 
               
               
                 Compound 
                 Compound 
                 Stock 
                 solving 
                 Test Range 
                 mediate 
               
               
                 I.D. 
                 Supplied 
                 Conc. 
                 Solvent 
                 (nM) 
                 Dilution 
               
               
                   
               
               
                 1* 
                 Solution 
                 10 mM 
                 DMSO 
                   3-200,000 
                 10% 
               
               
                   
                   
                   
                   
                   
                 DMSO 
               
               
                   
                   
                   
                   
                   
                 in HDAC 
               
               
                   
                   
                   
                   
                   
                 Assay 
               
               
                   
                   
                   
                   
                   
                 Buffer 
               
               
                 SAHA 
                 Powder 
                 10 mM 
                 DMSO 
                 0.3-10,000 
                 10% 
               
               
                   
                   
                   
                   
                   
                 DMSO 
               
               
                   
                   
                   
                   
                   
                 in HDAC 
               
               
                   
                   
                   
                   
                   
                 Assay 
               
               
                   
                   
                   
                   
                   
                 Buffer 
               
               
                   
               
               
                 *Compound 1 is cloudy at 2 mM in 10% DMSO (The highest test point). 
               
               
                 **SAHA, and HDACi, is a positive control for HDACs. 
               
            
           
         
       
     
     Experimental Conditions 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Enzymes and Substrates 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Enzyme Used 
                   
               
               
                 Assay 
                 Catalog # 
                 (ng)/Reaction 
                 Substrate 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 HDAC1 
                 50051 
                 1.5 
                 10 
                 μM of 50037 
               
               
                 HADC3/NCOR2 
                 50003 
                 1.33 
                 10 
                 μM of 50037 
               
               
                 HDAC5FL 
                 50045 
                 1.25 
                 2 
                 μM of 50040 
               
               
                 HDAC6 
                 50006 
                 10 
                 10 
                 μM of 50037 
               
               
                 HDAC7 
                 50007 
                 0.3 
                 2 
                 μM of 50040 
               
               
                 HDAC8 
                 50008 
                 20 
                 2 
                 μM of 50040 
               
               
                 HDAC10 
                 50010 
                 1,300 
                 10 
                 μM of 50037 
               
               
                 HADC11 
                 50011 
                 400 
                 2 
                 μM of 50040 
               
               
                 Sirtuin 1 
                 50012 
                 400 
                 10 
                 μM of 50032 
               
               
                 Sirtuin 2 
                 50013 
                 5,600 
                 10 
                 μM of 50032 
               
               
                   
               
            
           
         
       
     
     Assay Conditions. A series of dilution of the test compounds were prepared with 10% DMSO in assay buffer and 5 μl of the dilution was added to a 50 μl reaction so that the final concentration of DMSO is 1% in all of reactions. All of the enzymatic reactions were conducted in duplicate at 37° C. for 30 minutes except of HDAC11 at room temperature for 3 hours. The 50 μl reaction mixture contains HDAC assay buffer, 5 μg BSA, an HDAC substrate, an HDAC enzyme and a test compound. After enzymatic reactions, 50 μl of HDAC Developer was added to each well and the plate was incubated at room temperature for an additional 20 minutes. Fluorescence intensity was measured at an excitation of 360 nm and an emission of 460 nm using a Tecan Infinite M1000 microplate reader. 
     Data Analysis. HDAC activity assays were performed in duplicates at each concentration. The fluorescent intensity data were analyzed using the computer software, Graphpad Prism. In the absence of the compound, the fluorescent intensity (F t ) in each data set was defined as 100% activity. In the absence of HDAC, the fluorescent intensity (F b ) in each data set was defined as 0% activity. Compound 1 has fluorescence at assay condition; therefore the fluorescent intensity at different concentration of compound 1 was defined as background (Fb). The percent activity in the presence of each compound was calculated according to the following equation: % activity=(F−F b )/(F t −F b ), where F=the fluorescent intensity in the presence of the compound. 
     The values of % activity versus a series of compound concentrations were then plotted using non-linear regression analysis of Sigmoidal dose-response curve generated with the equation Y=B+(T−B)/1+10 ((Log EC50−X)×Hill Slope) , where Y=percent activity, B=minimum percent activity, T=maximum percent activity, X=logarithm of compound and Hill Slope=slope factor or Hill coefficient. The IC 50  value was determined by the concentration causing a half-maximal percent activity. 
     Results of Effect of Compound 1 on HDAC Inhibition 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 HDAC1 Assay - Data for the Effect of Compound 1 on HDAC1 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 17721 
                 17257 
                 796 
                 803 
                 101.39 
                 98.61 
               
               
                 0.5 
                 17287 
                 17200 
                 796 
                 798 
                 98.80 
                 98.28 
               
               
                 1.0 
                 17083 
                 17178 
                 788 
                 786 
                 97.64 
                 98.21 
               
               
                 1.5 
                 16949 
                 17020 
                 830 
                 784 
                 96.72 
                 97.14 
               
               
                 2.0 
                 16879 
                 16826 
                 796 
                 779 
                 96.42 
                 96.10 
               
               
                 2.5 
                 16792 
                 17072 
                 827 
                 775 
                 95.81 
                 97.49 
               
               
                 3.0 
                 16943 
                 16784 
                 829 
                 802 
                 96.63 
                 95.68 
               
               
                 3.5 
                 16387 
                 17135 
                 866 
                 827 
                 93.12 
                 97.60 
               
               
                 4.0 
                 16140 
                 16336 
                 920 
                 868 
                 91.35 
                 92.53 
               
               
                 4.5 
                 16432 
                 16128 
                 1117 
                 1035 
                 92.01 
                 90.19 
               
               
                 5.3 
                 24780 
                 24451 
                 14884 
                 13403 
                 63.73 
                 61.76 
               
               
                   
               
            
           
         
       
     
       FIG. 3  corresponds to the results shown in Table 4. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 HDAC3/NCOR2 Assay - Data for the Effect of Compound 1 on 
               
               
                 HDAC3/NCOR2 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 10787 
                 10452 
                 805 
                 828 
                 101.71 
                 98.29 
               
               
                 0.5 
                 10928 
                 9694 
                 813 
                 976 
                 102.35 
                 89.76 
               
               
                 1.0 
                 10423 
                 10379 
                 812 
                 818 
                 98.01 
                 97.56 
               
               
                 1.5 
                 10752 
                 10231 
                 813 
                 803 
                 101.44 
                 96.12 
               
               
                 2.0 
                 10827 
                 10078 
                 809 
                 798 
                 102.25 
                 94.61 
               
               
                 2.5 
                 10718 
                 10173 
                 818 
                 803 
                 101.07 
                 95.51 
               
               
                 3.0 
                 10587 
                 10073 
                 831 
                 811 
                 99.62 
                 94.38 
               
               
                 3.5 
                 10362 
                 10080 
                 854 
                 824 
                 97.14 
                 94.27 
               
               
                 4.0 
                 11530 
                 10216 
                 927 
                 898 
                 108.31 
                 94.90 
               
               
                 4.5 
                 9872 
                 10001 
                 1467 
                 1091 
                 87.66 
                 88.97 
               
               
                 5.3 
                 20905 
                 22163 
                 13408 
                 10875 
                 89.40 
                 102.23 
               
               
                   
               
            
           
         
       
     
       FIG. 4  corresponds to the results shown in Table 5. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 HDAC5FL Assay - Data for the Effect of Compound 1 on HDAC5FL 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 4492 
                 4892 
                 345 
                 348 
                 95.40 
                 104.60 
               
               
                 0.5 
                 4686 
                 4386 
                 355 
                 343 
                 99.80 
                 92.90 
               
               
                 1.0 
                 4802 
                 4581 
                 341 
                 347 
                 102.59 
                 97.50 
               
               
                 1.5 
                 4835 
                 4874 
                 359 
                 342 
                 103.20 
                 104.10 
               
               
                 2.0 
                 5071 
                 4991 
                 344 
                 356 
                 108.64 
                 106.80 
               
               
                 2.5 
                 5068 
                 5006 
                 344 
                 354 
                 108.60 
                 107.17 
               
               
                 3.0 
                 4944 
                 4685 
                 342 
                 354 
                 105.76 
                 99.80 
               
               
                 3.5 
                 4773 
                 4686 
                 353 
                 389 
                 101.30 
                 99.30 
               
               
                 4.0 
                 4987 
                 4983 
                 449 
                 407 
                 104.91 
                 104.82 
               
               
                 4.5 
                 4570 
                 4514 
                 451 
                 398 
                 95.40 
                 94.11 
               
               
                 5.3 
                 9875 
                 10983 
                 7907 
                 5878 
                 68.63 
                 94.13 
               
               
                   
               
            
           
         
       
     
       FIG. 5  corresponds to the results shown in Table 6. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 HDAC7 Assay - Data for the Effect of Compound 1 on HDAC7 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 7528 
                 7176 
                 382 
                 377 
                 102.52 
                 97.48 
               
               
                 0.5 
                 7578 
                 7200 
                 394 
                 383 
                 103.11 
                 97.69 
               
               
                 1.0 
                 6756 
                 6763 
                 385 
                 386 
                 91.37 
                 91.47 
               
               
                 1.5 
                 7471 
                 7705 
                 389 
                 381 
                 101.63 
                 104.98 
               
               
                 2.0 
                 7679 
                 7196 
                 390 
                 380 
                 104.61 
                 97.68 
               
               
                 2.5 
                 7071 
                 7068 
                 385 
                 398 
                 95.80 
                 95.75 
               
               
                 3.0 
                 7083 
                 7269 
                 384 
                 392 
                 96.02 
                 98.69 
               
               
                 3.5 
                 7453 
                 6898 
                 397 
                 462 
                 100.73 
                 92.77 
               
               
                 4.0 
                 6801 
                 7568 
                 416 
                 534 
                 90.73 
                 101.73 
               
               
                 4.5 
                 7238 
                 7518 
                 554 
                 565 
                 95.78 
                 99.80 
               
               
                 5.3 
                 9692 
                 9912 
                 3002 
                 2871 
                 96.89 
                 100.04 
               
               
                   
               
            
           
         
       
     
       FIG. 6  corresponds to the results shown in Table 7. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 HDAC8 Assay - Data for the Effect of Compound 1 on HDAC8 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 3492 
                 3483 
                 346 
                 346 
                 100.14 
                 99.86 
               
               
                 0.5 
                 3541 
                 3581 
                 339 
                 342 
                 101.88 
                 103.15 
               
               
                 1.0 
                 3519 
                 3391 
                 349 
                 342 
                 101.02 
                 96.94 
               
               
                 1.5 
                 3539 
                 3456 
                 336 
                 331 
                 102.04 
                 99.40 
               
               
                 2.0 
                 3757 
                 3425 
                 338 
                 340 
                 108.80 
                 98.23 
               
               
                 2.5 
                 3451 
                 3428 
                 335 
                 341 
                 99.09 
                 98.36 
               
               
                 3.0 
                 3398 
                 2995 
                 337 
                 347 
                 97.28 
                 84.45 
               
               
                 3.5 
                 3808 
                 3407 
                 346 
                 366 
                 109.88 
                 97.12 
               
               
                 4.0 
                 3361 
                 3365 
                 433 
                 374 
                 94.14 
                 94.27 
               
               
                 4.5 
                 3045 
                 3090 
                 375 
                 364 
                 85.17 
                 86.60 
               
               
                 5.3 
                 6631 
                 8117 
                 4962 
                 4635 
                 58.33 
                 105.63 
               
               
                   
               
            
           
         
       
     
       FIG. 7  corresponds to the results shown in Table 8. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 HDAC10 Assay - Data for the Effect of Compound 1 on HDAC10 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 11695 
                 12141 
                 497 
                 507 
                 98.05 
                 101.95 
               
               
                 0.5 
                 10894 
                 12032 
                 492 
                 501 
                 91.08 
                 101.05 
               
               
                 1.0 
                 12341 
                 12402 
                 497 
                 492 
                 103.77 
                 104.31 
               
               
                 1.5 
                 12564 
                 12368 
                 525 
                 500 
                 105.57 
                 103.85 
               
               
                 2.0 
                 12262 
                 12573 
                 500 
                 497 
                 103.04 
                 105.77 
               
               
                 2.5 
                 12472 
                 12556 
                 500 
                 493 
                 104.90 
                 105.64 
               
               
                 3.0 
                 11935 
                 12471 
                 530 
                 521 
                 99.94 
                 104.64 
               
               
                 3.5 
                 11622 
                 12684 
                 501 
                 607 
                 96.95 
                 106.25 
               
               
                 4.0 
                 11588 
                 12318 
                 597 
                 547 
                 96.50 
                 102.89 
               
               
                 4.5 
                 11448 
                 12305 
                 623 
                 495 
                 95.38 
                 102.89 
               
               
                 5.3 
                 25769 
                 22285 
                 12210 
                 12714 
                 116.56 
                 86.05 
               
               
                   
               
            
           
         
       
     
       FIG. 8  corresponds to the results shown in Table 9. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 HDAC11 Assay - Data for the Effect of Compound 1 on HDAC11 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 2840 
                 2860 
                 426 
                 406 
                 99.59 
                 100.41 
               
               
                 0.5 
                 2761 
                 2530 
                 411 
                 423 
                 96.30 
                 86.81 
               
               
                 1.0 
                 2828 
                 2898 
                 425 
                 415 
                 98.93 
                 101.81 
               
               
                 1.5 
                 2765 
                 2851 
                 411 
                 406 
                 96.82 
                 100.35 
               
               
                 2.0 
                 2812 
                 2864 
                 408 
                 409 
                 98.75 
                 100.88 
               
               
                 2.5 
                 2672 
                 2655 
                 412 
                 408 
                 92.93 
                 92.24 
               
               
                 3.0 
                 2829 
                 2806 
                 417 
                 424 
                 98.95 
                 98.01 
               
               
                 3.5 
                 2719 
                 2712 
                 427 
                 463 
                 93.43 
                 93.14 
               
               
                 4.0 
                 2835 
                 2860 
                 467 
                 524 
                 96.12 
                 97.14 
               
               
                 4.5 
                 3289 
                 3064 
                 699 
                 617 
                 108.09 
                 98.85 
               
               
                 5.3 
                 6249 
                 5842 
                 2911 
                 3158 
                 132.07 
                 115.35 
               
               
                   
               
            
           
         
       
     
       FIG. 9  corresponds to the results shown in Table 10. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Sirtuin 1 Assay - Data for the Effect of Compound 1 on Sirtuin 1 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 5823 
                 5974 
                 412 
                 410 
                 97.91 
                 100.64 
               
               
                 0.5 
                 5627 
                 5940 
                 414 
                 420 
                 94.26 
                 99.92 
               
               
                 1.0 
                 5240 
                 5913 
                 422 
                 413 
                 87.25 
                 99.42 
               
               
                 1.5 
                 5980 
                 5273 
                 418 
                 457 
                 100.27 
                 87.48 
               
               
                 2.0 
                 5827 
                 5527 
                 411 
                 411 
                 97.98 
                 92.56 
               
               
                 2.5 
                 6028 
                 5987 
                 413 
                 416 
                 101.56 
                 100.81 
               
               
                 3.0 
                 6454 
                 5681 
                 422 
                 452 
                 108.86 
                 94.87 
               
               
                 3.5 
                 5782 
                 5964 
                 422 
                 426 
                 96.93 
                 100.23 
               
               
                 4.0 
                 5786 
                 5408 
                 442 
                 441 
                 96.69 
                 89.85 
               
               
                 4.5 
                 5976 
                 5697 
                 502 
                 524 
                 98.83 
                 93.79 
               
               
                 5.3 
                 7483 
                 7591 
                 2022 
                 1997 
                 99.02 
                 100.98 
               
               
                   
               
            
           
         
       
     
       FIG. 10  corresponds to the results shown in Table 11. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Sirtuin 2 Assay - Data for the Effect of Compound 1 on Sirtuin 2 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 3910 
                 3919 
                 413 
                 419 
                 99.87 
                 100.13 
               
               
                 0.5 
                 3835 
                 3981 
                 420 
                 413 
                 97.71 
                 101.89 
               
               
                 1.0 
                 3780 
                 3821 
                 406 
                 422 
                 96.21 
                 97.38 
               
               
                 1.5 
                 3858 
                 3954 
                 408 
                 410 
                 98.59 
                 101.33 
               
               
                 2.0 
                 3712 
                 3912 
                 420 
                 413 
                 94.20 
                 99.91 
               
               
                 2.5 
                 3729 
                 3788 
                 409 
                 420 
                 94.74 
                 96.43 
               
               
                 3.0 
                 3714 
                 3861 
                 405 
                 409 
                 94.53 
                 98.73 
               
               
                 3.5 
                 3806 
                 3856 
                 422 
                 417 
                 96.80 
                 98.23 
               
               
                 4.0 
                 3844 
                 3883 
                 425 
                 426 
                 97.71 
                 98.83 
               
               
                 4.5 
                 3717 
                 3811 
                 485 
                 480 
                 92.45 
                 95.14 
               
               
                 5.3 
                 5686 
                 5717 
                 2225 
                 2245 
                 98.64 
                 99.53 
               
               
                   
               
            
           
         
       
     
       FIG. 11  corresponds to the results shown in Table 12. 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 HDAC6 Assay - Data for the Effect of Compound 1 on HDAC6 
               
               
                 Activity 
               
            
           
           
               
               
               
               
            
               
                   
                 HDAC Activity 
                 Background 
                   
               
               
                   
                 (Fluorescence 
                 (Fluorescence 
               
               
                 Compound 1 
                 count) 
                 count) 
                 % Activity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 (Log [nM]) 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
                 Repeat1 
                 Repeat2 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No CPD 
                 5844 
                 5616 
                 773 
                 733 
                 102.29 
                 97.71 
               
               
                 0.5 
                 5998 
                 6074 
                 832 
                 737 
                 104.75 
                 106.28 
               
               
                 1.0 
                 6006 
                 5728 
                 747 
                 704 
                 106.10 
                 100.51 
               
               
                 1.5 
                 5541 
                 6126 
                 746 
                 706 
                 96.75 
                 108.50 
               
               
                 2.0 
                 5733 
                 5981 
                 748 
                 731 
                 100.33 
                 105.31 
               
               
                 2.5 
                 5678 
                 5677 
                 763 
                 709 
                 99.30 
                 99.28 
               
               
                 3.0 
                 5717 
                 5446 
                 758 
                 716 
                 100.06 
                 94.62 
               
               
                 3.5 
                 5575 
                 5616 
                 781 
                 735 
                 96.79 
                 97.61 
               
               
                 4.0 
                 5516 
                 5789 
                 828 
                 786 
                 94.62 
                 100.10 
               
               
                 4.5 
                 4994 
                 5418 
                 1081 
                 1030 
                 79.13 
                 87.65 
               
               
                 5.3 
                 8327 
                 9938 
                 4925 
                 4721 
                 70.40 
                 102.77 
               
               
                   
               
            
           
         
       
     
       FIG. 12  corresponds to the results shown in Table 13. 
     Results of Effect of SAHA on HDAC Inhibition 
     SAHA is an HDAC inhibitor (HDACi). It serves as a positive control for HDACs.  FIGS. 13-15  show the inhibitory effect of SAHA on the HDACs HDAC1, HDAC3/NCOR2, and HDAC6. SAHA also inhibited HDAC5FL, HDAC7, HDAC8, HDAC10, Sirtuin 1, and Sirtuin 2 (see Table 1). 
     In In vitro assays, compound 1 has activity versus CBP, PCAF, and GCN5. The EC 50 &#39;s of compound 1 for CBP, PCAF, and GCN5 are 2.75 μM, 29.04 μM and 49.31 μM, respectively. Additionally, compound 1 did not interfere with p300 and HDAC activity (HDAC 1, 3, 5, 6, 7, 8, 10, 11, and sirt1-2). Compound 1 also increases p300 activity as shown in  FIG. 16 . 
     Example 4 
     Pharmacokinetic Experiments with Compound 1 
     Compound 1 pharmacokinetic (PK) and blood-brain barrier (BBB) penetration capability was assayed. After i.p. and i.v. administration at 20 mg/kg to BALB/c mice, plasma and brain concentrations were determined by LC-MS/MS. The data in Table 14 indicates that compound 1 is rapidly absorbed in the brain (T max  at 15min). 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Pharmacokinetic parameters of Compound 1. 
               
            
           
           
               
               
               
            
               
                   
                 IP Administration 
                 IV Administration 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Parameters 
                 Plasma 
                 Brain 
                 Ratio* 
                 Plasma 
                 Brain 
                 Ratio* 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 T max  (h) 
                 0.25 
                 0.25 
                 — 
                 0.125 
                 0.125 
                 — 
               
               
                 C max  (ng/mL or ng/g) 
                 843 
                 4878 
                 5.8 
                 2132 
                 27892 
                 13.1 
               
               
                 AUC 0-t  (ng · h/mL or ng · h/g) 
                 806 
                 6493 
                 8.1 
                 1967 
                 22222 
                 11.3 
               
               
                 AUC 0-∞  (ng · h/mL or ng · h/g) 
                 813 
                 6564 
                 8.1 
                 2020 
                 22581 
                 11.2 
               
               
                 t½ (h) 
                 0.60 
                 0.63 
                 — 
                 0.70 
                 0.63 
                 — 
               
               
                 MRT (h) 
                 0.85 
                 1.03 
                 — 
                 0.84 
                 0.74 
                 — 
               
               
                 F (%) 
                 41.0 
                 29.2 
                 — 
                 — 
                 — 
                 — 
               
               
                   
               
               
                 *Ratio = brain/plasma 
               
               
                 YF2 EC 50 &#39;s for CBP, PCAF and GCN5 are: 2.75 μM, 29.04 μM and 49.31 μM, respectively 
               
            
           
         
       
     
     The amount of compound 1 in the brain was higher than that in the plasma with an AUC 0-t  ratio of 8.2 and 10.8 for i.p. and i.v. administration, respectively. The elimination half-lives of compound 1 in the brain and plasma were ˜40 min. The T max  values in the brain and plasma were similar, indicating that the distribution of compound 1 to the brain is also fast. Additionally, in acute toxicity experiments compound 1 did not induce any adverse effects up to 300 mg/kg (i.p.). 
     Pharmacokinetic properties of compound 1 dosed orally are shown in  FIG. 17  and Table 15, and indicate that the amount of compound 1 in the brain is higher than that in the plasma. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Oral pharmacokinetic parameters of Compound 1. 
               
            
           
           
               
               
            
               
                   
                 Oral Administration 
               
            
           
           
               
               
               
               
            
               
                 Parameters 
                 Plasma 
                 Brain 
                 Ratio* 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 T max   
                 (h) 
                 0.5 
                 1.0 
                 — 
               
               
                 C max   
                 (ng/mL or ng/g) 
                 177 
                 1008 
                 5.7 
               
               
                 AUC 0-t   
                 (ng · h/mL or ng · h/g) 
                 328 
                 2149 
                 6.6 
               
               
                 AUC 0-∞   
                 (ng · h/mL or ng · h/g) 
                 330 
                 2159 
                 6.5 
               
               
                 t½ 
                 (h) 
                 1.06 
                 0.99 
                 — 
               
               
                 MRT 
                 (h) 
                 1.50 
                 1.68 
                 — 
               
               
                   
               
            
           
         
       
     
     Example 5 
     Contextual Fear Conditioning Experiments 
     Contextual fear conditioning was performed to assess whether compound 1 is capable of enhancing memory. This type of cognitive test is much faster than other behavioral tasks that require multiple days of training and testing ( J Clin Invest,  2004. 114(11): 1624-34; herein incorporated by reference in its entirety). The conditioning chamber was in a sound-attenuating box. A clear Plexiglas window allowed the experimenter to film the mouse performance with a camera placed on a tripod and connected to the Freezeframe software (MED Ass. Inc.). To provide background white noise (72 dB), a single computer fan was installed in one of the sides of the sound-attenuating chamber. The conditioning chamber had a 36-bar insulated shock grid floor. The floor was removable, and after each experimental subject, it was cleaned with 75% ethanol and then with water. Only one animal at a time was present in the experimentation room. 
     Training consisted of a 2.5 min period of acclimatizing to the context, followed by pairing of a tone (2800 Hz, 85 dB, 30 s) with a coterminating foot shock (0.4 mA, 1 s) for the weak training protocol, or pairing of a tone (2800 Hz, 85 dB, 30 s) with a coterminating foot shock (0.8 mA, 2 s) for the strong training protocol. The mice remained in the chamber for an additional 30 sec after the end of the last pairing, after which they were returned to their home cages. Contextual fear conditioning was assayed 24 hr after training by replacing the animals in the conditioning context for a 5 min period, during which the incidence of freezing (immobile except for respiration) was recorded. 
     The stronger training protocol leads to learning saturation, whereby freezing/memory reaches it max (˜25-30% in WT animals) even if the foot shock is increased. On the other hand, the weaker training protocol leads to much less freezing (˜15%), which allows the more freezing in case there is an increase in memory. When the weaker protocol was used, compound 1 worked as a memory enhancer. 
     Freezing behavior, defined as the absence of all movement except for that necessitated by breathing, was scored using the Freezeview software. 
     To evaluate contextual fear learning, freezing was measured for 5 min (consecutively) in the chamber in which the mice was trained 24 hr after training. To evaluate cued fear learning, following contextual testing, the mice were placed in a novel context (triangular cage with smooth flat floor) for 2 min (pre-CS test), after which they were exposed to the CS for 3 min (CS test), and freezing was measured. Sensory perception of the shock was determined through threshold assessment. A sequence of single foot shocks was delivered to animals placed on the same electrified grid used for fear conditioning. Initially, a 0.1 mV shock was delivered for 1 sec, and the animal behavior was evaluated for flinching, jumping, and vocalization. At 30 sec intervals the shock intensity was increased by 0.1 mV to 0.7 mV and then returned to 0 mV in 0.1 mV increments at 30 sec intervals. Threshold to vocalization, flinching, and then jumping was quantified for each animal by averaging the shock intensity at which each animal manifests a behavioral response to the foot shock. 
     Vehicle WT and compound 1 treated mice showed similar freezing responses before the delivery of the foot shock (baseline) ( FIG. 18 ). However, 5 and 20 mg/kg compound 1 treated mice froze nearly twice as often as did WT vehicle mice 24 h after training protocol (a single pairing of a tone with a 0.35 mA foot shock). Finally, no difference was observed among different groups of mice in different sets of experiments in which we assessed sensory threshold in the presence of vehicle or compound 1 (YF2) alone ( FIG. 19 ). 
     Based on the results obtained during the fear conditioning tests, it was decided to determine the kinetics of compound 1 in blood to verify the best time point for treatment. To this purpose, compound 1 (20 mg/kg. i.p.) was administered and then sampled blood from tails at different time points. The kinetics of compound 1 shows a peak around 30 minutes post-injection ( FIG. 20 ). 
     Compound 1, a Histone Acetyltransferase (HAT) Activator of the invention, is a good drug candidate to enhance memory and cognition in subjects without neurodegenerative diseases. When compound 1 (YF2)was administered to mice (i.p.), the western blot showed that it not only crosses the BBB, but also increases histone 3 acetylation levels of the hippocampus ( FIG. 21 ). 
     Compound 1 was then tested to ascertain increases in histone acetylation in mouse hippocampus. The compound was i.p. administered at 20 mg/Kg, mice were sacrificed 30 min later, and hippocampi were removed and quickly frozen for WB analysis. As shown in  FIG. 22 , compound 1 (YF2) increased acetylation of histone lysines that were shown to be involved in memory formation (H3K4, H3K9, H3K14, H4K5, H4K8, H4K12, H4K16, and H2B) ( Neuron,  2004, 42(6): 947-59;  Science  328(5979): 753-6; each herein incorporated by reference in its entirety). 
     Example 6 
     Compound 1 Rescues AO-Induced Reduction in BDNF Levels 
     Compound 1 increases levels of BDNF, a key protein necessary for activity-dependent plasticity and memory. CBP was shown to facilitate the transcription of key proteins necessary for activity-dependent plasticity and memory (Korzus, E., M. G. Rosenfeld, and M. Mayford,  CBP histone acetyltransferase activity is a critical component of memory consolidation.  Neuron, 2004. 42(6): p. 961-72; herein incorporated by reference in its entirety), such as brain-derived neurotrophic factor (BDNF), which is known to facilitate synaptic plasticity and memory formation (Cowansage, K. K., J. E. LeDoux, and M. H. Monfils,  Brain - derived neurotrophic factor: a dynamic gatekeeper of neural plasticity.  Current molecular pharmacology, 2010. 3(1): p. 12-29; Caccamo, A., et al.,  CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer&#39;s disease.  Proc Natl Acad Sci USA, 2010. 107(52): p. 22687-92; each herein incorporated by reference in its entirety). Interestingly, BDNF was proposed to play a role in AD pathogenesis, with reduced BDNF levels detected in brains of AD patients and AD animal models (Hock, C., et al.,  Region - specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain - derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas.  Archives of neurology, 2000. 57(6): p. 846-51; Connor, B., et al.,  Brain - derived neurotrophic factor is reduced in Alzheimer&#39;s disease.  Brain research. Molecular brain research, 1997. 49(1-2): p. 71-81; Garzon, D. J. and M. Fahnestock,  Oligomeric amyloid decreases basal levels of brain - derived neurotrophic factor  ( BDNF )  mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells.  The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 2007. 27(10): p. 2628-35; each herein incorporated by reference in its entirety). Thus, preliminary studies on Compound 1 efficacy were extended to to BDNF. BDNF levels in the hippocampi of Aβ-infused mice were measured compared to vehicle infused animals. Consistent with the decrease in BDNF levels in brains of AD patients and animal models of AD, a reduction of BDNF levels following Aβ infusion was found ( FIG. 23 ). This effect was rescued by Compound 1 (20 mg/kg, i.p., 90 min before harvesting the hippocampi,  FIG. 23 ). Interestingly, Compound 1 increased BDNF levels in vehicle-infused mice ( FIG. 23 ), consistent with the observation that basal levels of BDNF are increased following stimulation of the gene transcription machinery relevant to memory formation (Arancio, O. and M. V. Chao,  Neurotrophins, synaptic plasticity and dementia.  Current Opinion in Neurobiology, 2007. 17(3): p. 325-30; herein incorporated by reference in its entirety). 
     Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are considered to be within the scope of this invention, and are covered by the following claims. 
     Although the invention has been described and illustrated in the foregoing illustrative embodiments, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the details of implementation of the invention can be made without departing from the spirit and scope of the invention, which is limited only by the claims that follow. Features of the disclosed embodiments can be combined and rearranged in various ways to obtain additional embodiments within the scope and spirit of the invention.