Abstract:
The invention provides a method of identifying biologically active compounds comprising: (a) designing a first library of compounds of formula (1) to scan molecular diversity wherein each compound of the library has at least two pharmacophoric groups R1 to R5 as defined below and wherein compound of the library has same number of pharmacophoric groups; (b) assaying the first library of compounds in one or more biological assay(s); and (c) designing a second library wherein each compound of the second library contains one or more additional pharmacophoric group with respect to the first library; such that the/each component of the first and second library is a compound of formula (1).

Description:
FIELD OF THE INVENTION 
       [0001]    The invention relates to a method of identifying biologically active compounds, libraries of compounds. 
       BACKGROUND 
       [0002]    Small molecules involved in molecular interactions with a therapeutic target, be it enzyme or receptor, are often described in terms of binding elements or pharmacophoric groups which directly interact with the target, and non-binding components which form the framework of the bioactive molecule. In the case of peptide ligands or substrates for instance, usually a number of amino acid side chains form direct interactions with their receptor or enzyme, whereas specific folds of the peptide backbone (and other amino acid residues) provide the structure or scaffold that controls the relative positioning of these side chains. In other words, the three dimensional structure of the peptide serves to present specific side chains in the required fashion suitable for binding to a therapeutic target. The problem is that such models do not allow for rapid identification of drug candidates owing to the necessity to synthesize an enormous amount of compounds to identify potential active compounds. 
         [0003]    A pharmacophoric group in the context of these libraries is an appended group or substituent, or part thereof, which imparts pharmacological activity to the molecule. 
         [0004]    Molecular diversity could be considered as consisting of diversity in pharmacophoric group combinations (diversity in substituents) and diversity in the way these pharmacophoric groups are presented (diversity in shape). Libraries of compounds in which either diversity of substituents, or diversity of shape, or both of these parameters are varied systematically are said to scan molecular diversity. 
         [0005]    Carbohydrate scaffolds provide a unique opportunity to create libraries of structurally diverse molecules, by varying the pharmacophoric groups, the scaffold and the positions of attachment of the pharmacophoric groups in a systematic manner. Such diversity libraries allow the rapid identification of minimal components or fragments containing at least two pharmacophoric groups required for an interaction with a biological target. These fragments can be further optimized to provide potent molecules for drug design. Therefore these types of carbohydrate libraries provide an excellent basis for scanning molecular diversity. 
         [0006]    In previous applications (WO2004014929 and WO2003082846) we demonstrated that arrays of novel compounds could be synthesized in a combinatorial manner. The libraries of molecules described in these inventions were synthesized in a manner such that the position, orientation and chemical characteristics of pharmacophoric groups around a range of chemical scaffolds, could be modified and/or controlled. These applications demonstrate the synthesis and biological activity of a number of new chemical entities. 
         [0007]    Many drug discovery strategies fail owing to lack of knowledge of the bioactive conformation of, or the inability to successfully mimic the bioactive conformation of the natural ligand for a receptor. Libraries of compounds of the present invention allow for the systematic “scanning” of conformational space to identify the bioactive conformation of the target. 
         [0008]    Typically in the prior art, libraries based on molecular diversity are generated in a random rather than a systematic manner. This type of random approach requires large number of compounds to be included in the library to scan for molecular diversity. Further, this approach may also result in gaps in the model because of not effectively accessing all available molecular space. 
         [0009]    Therefore, one of the problems in the prior art is the necessity to synthesize an enormous amount of compounds to identify potential active compounds. Attempts have been made to develop peptidomimetics using sugar scaffolds by Sofia et al. ( Bioorganic  &amp;  Medicinal Chemistry Letters  (2003) 13, 2185-2189). Sofia describes the synthesis of monosaccharide scaffolds, specifically containing a carboxylic acid group, a masked amino group (N 3 ) and a hydroxyl group as substitution points on the scaffold, with the two remaining hydroxyl groups being converted to their methyl ethers. Sofia teaches a specific subset of scaffolds not encompassed by the present invention and does not contemplate methods to simplify the optimization of pharmacophoric groups. 
         [0010]    Therefore there remains a need to provide a method of effectively scanning libraries designed from compounds with a wider range of different pharmacophoric groups. 
         [0011]    The present invention is directed to a method of drug design utilizing iterative scanning libraries, resulting in surprisingly efficient identification of drug candidates, starting from a selected number of pharmacophores (e.g., two) in the first library and designing subsequent libraries with additional pharmacophores based on SAR information from the first library. 
         [0012]    The invention can provide a new method for the rapid identification of active molecules. 
         [0013]    In an embodiment, and to demonstrate the versatility of our invention, one of the G-protein coupled receptors (GPCR&#39;s) was chosen as a target: the somatostatin receptor (SST receptor). The tetradecapeptide somatostatin is widely distributed in the endocrine and exocrine system, where it has an essential role in regulating hormone secretion [1-3]. Five different subtypes have been identified to date (SST1-5), which are expressed in varying ratios throughout different tissues in the body. Somatostatin receptors are also expressed in tumours and peptide analogues of somatostatin affecting mainly SST5, such as ocreotide, lanreotide, vapreotide and seglitide [4-7] have antiproliferative effects. They are used clinically for the treatment of hormone-producing pituitary, pancreatic, and intestinal tumours. SST5 is also implicated in angiogenesis, opening up the possibility of developing antiangiogenic drugs that act on the SST5 receptor, for example for the use in oncology. The “core sequence” in somatostatin responsible for its biological activity is Ph-Trp-Lys (FWK), representing a motif of two aromatic groups and a positive charge, which is found in almost all SST receptor active compounds. 
         [0014]    It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country. 
       SUMMARY OF THE INVENTION 
       [0015]    In one form, the invention provides a method of identifying biologically active compounds comprising:
       (a) designing a first library of compounds of formula 1 to scan molecular diversity wherein each compound of the library has at least two pharmacophoric groups R1 to R5 as defined below and wherein compound of the library has same number of pharmacophoric groups;   (b) assaying the first library of compounds in one or more biological assay(s); and   (c) designing a second library wherein each compound of the second library contains one or more additional pharmacophoric group with respect to the first library;
 
such that the/each component of the first and second library is a compound of formula 1:
       
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein the ring may be of any configuration;
 
Z is sulphur, oxygen, CH 2 , C(O), C(O)NR A , NH, NR A  or hydrogen, in the case where Z is hydrogen then R 1  is not present, R A  is selected from the set defined for R 1  to R 5 , or wherein Z and R1 together form a heterocycle,
 
X is oxygen or nitrogen providing that at least one X of Formula I is nitrogen, X may also combine independently with one of R 1  to R 5  to form an azide,
 
R 1  to R 5  are independently selected from the following non-pharmacophoric groups H, methyl and acetyl, and pharmacophoric groups, R 1  to R 5  are independently selected from the group which includes but is not limited to C 2  to C 20  alkyl or acyl excluding acetyl; C 2  to C 20  alkenyl, alkynyl, heteroalkyl; C 5  to C 20  aryl, heteroaryl, arylalkyl or heteroarylalkyl, which is optionally substituted, and can be branched or linear,
 
or wherein X and the corresponding R moiety, R 2  to R 5  respectively, combine to form a heterocycle.
 
         [0019]    In another form, the invention comprises biologically active compounds when identified by the method described above. 
         [0020]    In a preferred embodiment, the invention relates to said method wherein in the first library, three of the substituents R 1 -R 5  are non-pharmacophoric groups and are selected from hydrogen or methyl or acetyl. 
         [0021]    In a preferred embodiment, the invention relates to said first method wherein in the first library, two of the substituents R 1 -R 5  are non-pharmacophoric groups and are selected from hydrogen or methyl or acetyl. 
         [0022]    In a preferred embodiment, the invention relates to said first method wherein Z is sulphur or oxygen; 
         [0023]    In a preferred embodiment, the invention relates to said first method wherein at least one of the pharmacophoric groups is selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl or acyl 
         [0024]    In a preferred embodiment, the invention relates to a library of compounds selected from compounds of formula 1 wherein in the first library, three of the non-pharmacophoric groups R 1 -R 5  are hydrogen or methyl or acetyl when used according to said first method. 
         [0025]    In a preferred embodiment, the invention relates to a library of compounds selected from compounds of formula 1 wherein in the second library, two of the non-pharmacophoric groups R 1 -R 5  are hydrogen or methyl or acetyl when used according to said first method. 
         [0026]    In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 
         [0000]    
       
                 
         
             
             
         
       
     
         [0027]    In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the gluco- or galacto- or allo-configuration. 
         [0028]    In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 wherein the/each compound is of the galacto-configuration. 
         [0029]    In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the gluco-configuration. 
         [0030]    In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the alit configuration. 
         [0031]    In a preferred embodiment, the invention relates to said first method wherein designing the library comprises molecular modeling to assess molecular diversity. 
         [0032]    In a preferred embodiment, the invention relates to said first method wherein R 1  to R 5  optional substituents include OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted. 
         [0033]    The term “halogen” denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. 
         [0034]    The term “alkyl” used either alone or in compound words such as “optionally substituted alkyl”, “optionally substituted cycloalkyl”, “arylalkyl” or “heteroarylalkyl”, denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl), 5-methylhexyl, 1-methylhexyl, 2,2-dimethypentyl, 3,3 dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3 or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2 pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. 
         [0035]    The term “alkylene” used either alone or in compound words such as “optionally substituted alkylene” denotes the same groups as “alkyl” defined above except that an additional hydrogen has been removed to form a divalent radical. It will be understood that the optional substituent may be attached to or form part of the alkylene chain. 
         [0036]    The term “alkenyl” used either alone or in compound words such as “optionally substituted alkenyl” denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as defined above, preferably C2-6 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3 cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. 
         [0037]    The term “alkynyl” used either alone or in compound words, such as “optionally substituted alkynyl” denotes groups formed from straight chain, branched, or mono- or poly- or cyclic alkynes, preferably C 2-6 alkynyl. 
         [0038]    Examples of alkynyl include ethynyl, 1-propynyl, 1- and 2butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4pentynyl, 2-hexynyl, 3-hexylnyl, 4-hexynyl, 5-hexynyl, 10-undecynyl, 4-ethyl-l-octyn-3-yl, 7-dodecynyl, 9-dodecynyl, 10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11tridecynyl, 3-tetradecynyl, 7-hexadecynyl, 3-octadecynyl and the like. 
         [0039]    The term “alkoxy” used either alone or in compound words such as “optionally substituted alkoxy” denotes straight chain or branched alkoxy, preferably C1-7 alkoxy. Examples of alkoxy include methoxy, ethoxy, npropyloxy, isopropyloxy and the different butoxy isomers. 
         [0040]    The term “aryloxy” used either alone or in compound words such as “optionally substituted aryloxy” denotes aromatic, heteroaromatic, arylalkoxy or heteroaryl alkoxy, preferably C6-13 aryloxy. Examples of aryloxy include phenoxy, benzyloxy, 1-napthyloxy, and 2-napthyloxy. 
         [0041]    The term “acyl” used either alone or in compound words such as “optionally substituted acyl” or “heteroarylacyl” denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthlpropanoyl and naphthylbutanoyl); aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacrylyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and naphthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienyglyoxyloyl. 
         [0042]    The term “aryl” used either alone or in compound words such as “optionally substituted aryl”, “arylalkyl” or “heteroaryl” denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyrdyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, pyrrolyl, furanyl, imadazolyl, pyrrolydinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. Preferably, the aromatic heterocyclic ring system contains 1 to 4 heteroatoms independently selected from N, O and S and containing up to 9 carbon atoms in the ring. 
         [0043]    The term “heterocycle” used either alone or in compound words as “optionally substituted heterocycle” denotes monocyclic or polycyclic heterocyclyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated to 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidin or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazoyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl. 
         [0044]    In a preferred embodiment, the invention relates to said first method wherein the compounds are synthesized. 
         [0045]    In a preferred embodiment, the invention relates to said first method wherein the biological assays are selected from peptide ligand class of GPCRs. 
         [0046]    In another aspect the invention provides a compound according to formula 1 in which at least one X is nitrogen, and said X is combined with the corresponding R 2 -R 5  to form a heterocycle. The synthesis of the heterocyclic components of the present invention is disclosed in WO 2004/022572. 
         [0047]    In a preferred embodiment, the invention provides a compound according to formula 1 wherein X and R 2  combine to form a heterocycle. 
         [0048]    In a preferred embodiment, the invention provides a compound according to formula 1 wherein the heterocycle is heteroaryl, including triazoles, benzimidazoles, benzimidazolone, benzimidazolothione, imidazole, hydantoine, thiohydantoine and purine. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0049]    The embodiments of the invention will be described with reference to the following examples. Where appropriate, the following abbreviations are used. 
       Ac Acetyl 
       [0000]    
       
         DTPM 5-Acyl-1,3-dimethylbarbiturate 
         Ph Phenyl 
         TBDMS t-Butyldimethylsilyl 
         TBDPS t-Butyldiphenylsilyl 
         Bn benzyl 
         Bz benzoyl 
         Me methyl 
         DCE 1,2-dichloroethane 
         DCM dichloromethane, methylene chloride 
         Tf trifluoromethanesulfonyl 
         Ts 4-methylphenylsulfonyl, p-toluenesulfonyl 
         DMF N,N-dimethylformamide 
         DMAP N,N-dimethylaminopyridine 
         α,α-DMT α,α-dimethoxytoluene, benzaldehyde dimethyl acetal 
         DMSO dimethylsulfoxide 
         DTT dithiothreitol 
         DMTST Dimethyl(methylthio)sulphoniumtrifluoro-methanesulphonate 
         TBAF tetra-n-butylammonium fluoride 
       
     
       Part A: Preparation of Building Blocks: 
       [0068]    In order to fully enable the invention, there is described below methods for the preparation of certain building blocks used in the preparation of the compounds of the invention. The building blocks described are suitable for both solution and solid phase synthesis of the compounds of the invention. 
       Example A 
     Synthesis of a 2,4 Dinitrogen Containing Galactopyranoside Building Block 
       [0069]    
       
                 
         
             
             
         
       
     
         [0000]    Conditions: (i) α,αdimethoxytoluene (α,α-DMT), p-toluenesulphonic acid (TsOH), acetonitrile (MeCN), 76° C., 85%; (ii) Benzoylchloride (BzCl), triethylamine; DCM, 99%; (iii) methanol (MeOH)/MeCN/water, TsOH, 75° C., 98%; (iv) t-butyldiphenylsilylchloride (TBDPS-Cl), imidazole, pyridine, 120° C., 99%; (v) Tf 2 O, pyridine, DCM, 0° C., 100%; (b) NaN 3 , DMF, 16 hr, RT, 99%. 
       Example B 
     Synthesis of a 3-Nitrogen Containing Gulopyranoside Building Block 
       [0070]    
       
                 
         
             
             
         
       
     
         [0000]    Conditions: (i) (a) trifluoromethanesulfonic anhydride (Tf 2 O), pyridine, −20° C., dichloromethane (DCM), 1 hour, 100%, (b) sodium azide (NaN 3 ), N,N-dimethylformamide (DMF), 50° C., 5 hours, quantitative; (ii) TsOH, MeCN/MeOH/water (12:3:1), 90° C., 6 hours, 88% (iii) TBDPSCl, DMAP, pyridine, 120° C., 12 hours, 93% 
       Example C 
     Synthesis of a 2,6-Dinitrogen Substituted Glucopyranoside Building Block 
       [0071]    
       
                 
         
             
             
         
       
     
       Example D 
     Synthesis of a 2-Nitrogen Containing Tallopyranoside Building Block 
       [0072]    
       
                 
         
             
             
         
       
     
       Example E 
     Synthesis of Two 3-Nitrogen Containing Altropyranoside Building Block 
       [0073]    
       
                 
         
             
             
         
       
     
       Example F 
     Synthesis of a 2-Nitrogen Containing Glucopyranoside Building Block 
       [0074]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
       Example G 
     Synthesis of a 2-Nitrogen Containing Allopyranoside Building Block 
       [0075]    
       
                 
         
             
             
         
       
     
         [0076]    The Solid Phase Library Synthesis of Sugars is illustrated in Scheme 1. 
         [0077]    The reaction conditions are as follows: 
         [0000]    (A) 2P compound synthesis: R 1 =R 2 =OMe;
 
i) 2-naphthalene methanol, DMTST, DCM; ii) TCA-Wang resin, BF 3 .Et 2 O, DCM; iii) NaOMe, methanol; iv) a. KOtBu, DMF; b. MeI, DMF; v) HF.‘proton sponge’, AcOH, DMF, 65° C.; vi) a. KOtBu, DMF; b. MeI, DMF; vii) 1,4-dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-β-Ala-OH, DIPEA, DMF; ix) piperidine/DMF (1/4); x) TFA, Et 3 SiH, DCM
 
(B) 3P compound synthesis: R 1 =methyl-2-naphthyl, R 2 =OMe;
 
i) 2-naphthalene methanol, DMTST, DCM; ii) TCA-Wang resin, BF 3 .Et 2 O, DCM; iii) NaOMe, methanol; iv) a. KOtBu, DMF; b. 2-bromomethyl-naphthalene, DMF; v) HF.‘proton sponge’, AcOH, DMF, 65° C.; vi) a. KOtBu, DMF; b. MeI, DMF; vii) 1,4-dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-β-Ala-OH, DIPEA, DMF; ix) piperidine/DMF (1/4); x) TFA, Et 3 SiH, DCM
 
(C) 4P compound synthesis: R 1 =methyl-2-naphthyl, R 2 =4-chlorobenzyl
 
i) 2-naphthalene methanol, DMTST, DCM; ii) TCA-Wang resin, BF 3 .Et 2 O, DCM; iii) NaOMe, methanol; iv) a. KOtBu, DMF; b. 2-bromomethyl-naphthalene, DMF; v) HF.‘proton sponge’, AcOH, DMF, 65° C.; vi) a. KOtBu, DMF; b. 4-chlorobenzylbromide, DMF; vii) 1,4-dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-β-Ala-OH, DIPEA, DMF; ix) piperidine/DMF (1/4); x) TFA, Et 3 SiH, DCM
 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0078]    The synthesis of the Allose 2,6N building block is illustrated in Scheme 2. The reaction conditions are as follows: 
         [0079]    i) p-methoxybenzaldehyde dimethylacetal, camphorsulfonic acid, N,N-dimethylformamide (DMF); ii) Tf 2 O, pyridine, dichloromethane (DCM); iii) tetrabutylammonium benzoate, DMF, 55° C.; iv) BH 3 .THF, Bu 2 BOTf, DCM; v) methanesulfonylchloride, pyridine, DCM; vi) sodium azide, DMF, 85° C.; vii) sodium methanolate (NaOMe), methanol; viii) n-butanol, ethylene diamine, reflux; ix) DTPM reagent, methanol; x) benzoic anhydride, pyridine; xi) trifluoroacetic acid, triethylsilane, DCM 
       Designing Libraries: 
       [0080]    The design of the libraries is based on the presentation of a positive charge and a varying number of aromatic substituents in different spatial arrangements on a monosaccharide scaffold. Starting with a positive charge and one aromatic displayed on the core scaffold, actives from this first library were elaborated on by further variation and addition of more aromatic substituents to quickly identity highly active molecules. 
         [0081]    The first library of compounds comprises two pharmacophoric groups, known as a 2P library, in particular, one containing an aromatic and a positive charge. The library was designed such that each molecule presents two pharmacophoric groups in different relative orientation or presentation (e.g., distance, relative angle, i.e. relative position in space is different). 
         [0082]    Actives from this library were identified and SAR information from this library was used to design subsequent library of compounds wherein each compound may include three pharmacophoric groups, known as a 3P library. Subsequent libraries with four pharmacophoric groups are called 4P library, etc. 
         [0083]    Members of significantly improved activity were identified out of the second library and were selected for further drug development. 
         [0084]    The method of the invention includes real and virtual libraries. 
         [0085]    Thus, the molecules according to formula 1 are well suited for generating iterative scanning libraries, starting from a selected number of pharmacophores (eg, two) in the first library and designing subsequent libraries with additional pharmacophores based on SAR information from the first library, thereby assisting in delineating pharmacophores. 
         [0086]    The 2P and 3P library of compounds were synthesized according to the building blocks as described in Examples A-G. 
         [0087]    The 2P library (Table 1) was designed to scan molecular diversity for 2P molecules, comprising an aromatic and a positive charge. 
         [0088]    The 2P library was screened for biological activity and the results are given in Table 1. 
         [0089]    Similarly, the 3P library was designed to scan molecular diversity for 3P molecules. Design of 3P library resulted from SAR obtained from 2P library in Table 1. 
         [0090]    The 3P library was screened for biological activity and the results are given in Table 2. 
         [0091]    A visual analysis of the results according to Table 1 (2P library) and Table 2 (3P Library) indicates that: 
         [0000]    1. 1, 2 allose substitution according to formula 3 (and Scaffold C/D) presents the most active arrangement of molecules in the library wherein Z is oxygen, R 1  is naphthyl and R 2  is propylamine or ethylamine. 
         [0092]    These compounds represent most actives at low nM range, and are suitable candidates for further drug development. 
         [0000]    2. R 1  as naphthyl is more active than the corresponding p-chlorobenzyl substituent.
 
3. 1, 2 allose according to formula 3 (Scaffold C/D) is more active than the corresponding 1, 2 glucose conformation (Scaffold A/B).
 
4. 1, 2 substitution according to formula 3 (Scaffold C/D) is more active than the corresponding 2, 6 substitution according to formula 4 (Scaffold G)
 
5. R 2  as propylamine and ethylamine are more active than methylamine wherein Z, R 1  and R 2  are as described above.
 
6. 2, 3 allose substitution according to formula 3 (Scaffold C/D) presents the more actives wherein R 2  is ethylamine, and R 3  is p-chlorobenzyl compared to corresponding R 2  as propylamine and ethylamine wherein R3 is p-chlorobenzyl substituent, and also wherein R 2  is methylamine, ethylamine or propylamine and R3 is naphthyl.
 
7. 2, 3 glucose substitution according to formula 3 (scaffold A/B) presents the more actives wherein  R2  is propylamine and R 3  is naphthyl compared to corresponding R 2  as methylamine or ethylamine, and also wherein R 2  is methylamine, ethylamine or propylamine and R 3  is p-chlorobenzyl.
 
8. 2, 4 and 3, 4 substitutions according to formula 3 (Scaffold G) present the least actives.
 
       Part B: Biological Assays 
     Example H 
     In Vitro Screening of Compounds Against Somatostatin Subtypes SSTR-1 to SSTR-5 
     General Method 
       [0093]    Receptor membrane preparations containing the desired cloned receptor (for example cloned human somatostatin receptor subtype 5, SSTR5) and radio-labeled ligand were diluted at the concentration required for testing and according to the specific parameters associated with the selected receptor-ligand combination, including receptor B max , ligand K d  and any other parameters necessary to optimize the experimental conditions. When tested for competition activity to the reference ligand, “compound” was mixed with membrane suspension and the radiolabeled reference ligand (with or without an excess of unlabeled ligand to the receptor for determination of non-specific binding) and incubated at the temperature required by internal standard operating procedures. Following incubation, the binding reaction was stopped by the addition of ice-cold washing buffer and filtered on appropriate filters, which are then counted. Data analysis and curve-fitting was performed with XLfit (IDBS). 
       Preparation of Compounds 
       [0094]    10 mM solutions of test compounds in 100% DMSO were prepared. ˜160 μl was used for each dilution (20 μl/well in triplicate). 
         [0095]    A 1.25 mM assay stock was prepared by making a 1:8 dilution of the 10 mM solution. To 30 μL of the 10 mM solution was added 210 μL milli-Q H 2 O. A 1:5 dilution series in milli-Q H 2 O was then prepared. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Final concentration 
                 Final concentration 
               
               
                   
                 in SST4 assay 
                 in SST5 assay 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 A. 
                 240 μL of 1.25 mM 
                 0.25 mM 
                 0.125 mM 
               
               
                 B. 
                 48 μL A + 192 μL mQ 
                 0.05 mM 
                 0.025 mM 
               
               
                 C. 
                 24 μL B + 192 μL mQ 
                 0.01 mM 
                 0.005 mM 
               
               
                 etc 
               
               
                   
               
             
          
         
       
     
         [0096]    Assays were performed in triplicate at each concentration within the 1:5 dilution series: 250 μM, 50 μM, 10 μM, 2 mM, 0.4 μM, 0.08 μM, 0.016 μM, 0.0032 μM, etc. (for SST4 assay) and 125 μM, 10 μM, 2 μM, 1 μM, 0.5. μM, etc (for SST5 assay). 
       Filter Plate Assay for SST5 Receptor 
       [0097]    Human SST5 somatostatin receptor was transfected into HEK-293 EBNA cells. Membranes were suspended in assay buffer (50 mM Tris-HCl, 1 mM EGTA, 5 mM MgCl 2 , 10% sucrose, pH 7.5). The receptor concentration (B max ) was 0.57 pmol/mg protein K d  for [ 125 I]SST-14 Binding 0.31 nM, volume 0.4 ml per vial (400 microassays/vial), and protein concentration 1.03 mg/ml. 
         [0098]    After thawing the frozen receptor preparation rapidly, receptors were diluted with binding buffer, homogenized, and kept on ice.
       1. Use Multiscreen glass fiber filter plates (Millipore, Cat No MAFCNOB10) precoated with 0.5% PEI for ˜2 hr at 4° C. Before use add 200 μl/well assay buffer and filter using Multiscreen Separation System.   2. Incubate 5.5 μg of membranes (40 μl of a 1:40 dilution), buffer and [ 125 I]SST-14 (4 nM, ˜80 000 cpm, 2000 Ci/mmol) in a total volume of 200 μl for 60 min at 25° C. Calculate IC50 for SST-14 (a truncated version of the natural ligand SST-28) (Auspep, Cat No 2076) and SST-28 (Auspep, Cat No 1638). Prepare serial dilutions (1:5) of compounds, as described above and instead of adding SST-14 in well, add 20 μl of compounds (Table 3).   3. Filter using Multiscreen Separation System with 5×0.2 ml ice-old Assay buffer.   4. Remove the plastic underdrain and dry plate in oven for 1 hr at 40° C.   5. Seal tape to the bottom of the plate.   6. Add 50 μl/well scintillant (Supermix, Wallac, Cat No 1200-439).   7. Seal and count in the BJET, program 2.       
 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 3 
               
               
                   
                   
               
               
                   
                   
                   
                   
                 Compounds 
               
               
                   
                 Volume (ul) 
                 TB 
                 NSB 
                 testing 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Membranes (5.5 μg/well) 
                 40 
                 40 
                 40 
               
               
                   
                 Radio-labeled label (~80 000 
                 40 
                 40 
                 40 
               
               
                   
                 cpm, ~4 nM) 
               
               
                   
                 Unlabeled ligand 
                 — 
                 20 
                 — 
               
               
                   
                 mQH 2 O 
                 20 
                 — 
                 — 
               
               
                   
                 Compounds 
                   
                   
                 20 
               
               
                   
                 Assay buffer 
                 100 
                 100 
                 100 
               
               
                   
                 Total volume (μl) 
                 200 
                 200 
                 200 
               
               
                   
                   
               
               
                   
                 TB: total binding 
               
               
                   
                 NSB: non-specific binding 
               
             
          
         
       
     
       Part C: General Experimental Methods 
     Example I 
     HPLC Method for Compounds in Tables 1 and 2 
       [0106]    The HPLC separation of compounds in Tables 1 and 2 was conducted under Method A or Method B as shown below. 
       Method A 
     Column: Agilent SB Zorbax C18 4.6×50 mm (5 μm, 80 Å) 
       [0107]    LC mobile phase:
 
5% aqueous MeCN/1 min
 
       100% MeCN/7-12 min 
     Method B 
     Column: Agilent SB Zorbax C18 4.6×50 mm (5 μm, 80 Å) 
       [0108]    LC mobile phase: 
       5% aq MeCN/1 min 
     30% aq MeCN/3 min 
     40% aq MeCN/12 min 
     100% MeCN/13-15 min 
     Key to Building Blocks for Tables 1 and 2 
       [0109]    Table 1: * % SST5 radio-ligand binding displaced at conc (μM) for 2P library of compounds
 
Table 2: * % SST5 radio ligand binding displaced at conc (μM) for 3P library of compounds; R 4 =X30; compounds 60-63, 119 and 156-159 are comparative compounds from 2P library
 
“++”: % SST5 radio-ligand binding displaced at conc (μM) &gt;60%
 
“+”: % SST5 radio-ligand binding displaced at cone (μM) 60&gt;+&gt;40%
 
“−”: % SST5 radio-ligand binding displaced at cone (μM) −&lt;40%
 
Blank: not determined
 
RT: retention time/minutes
 
M+H: mass ion+1
 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Biological activity of example 2P library 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 conc 
                 conc 
                 conc 
                   
                   
               
               
                 Object ID 
                 Scaffold 
                 R1 
                 R2 
                 R3 
                 R4 
                 R5 
                 500 
                 250 
                 50* 
                 RT 
                 M + H 
               
               
                   
               
             
          
           
               
                 1 
                 E 
                 — 
                 X15 
                 X2 
                 X30 
                 X24 
                   
                   
                   
                 3.24 
                 449.58 
               
               
                 2 
                 A 
                 X7 
                 X20 
                 X24 
                 X30 
                 X24 
                   
                   
                   
                 3.4 
                 383.46 
               
               
                 3 
                 A 
                 X7 
                 X15 
                 X24 
                 X30 
                 x24 
                   
                   
                   
                 3.42 
                 397.48 
               
               
                 4 
                 E 
                 — 
                 X20 
                 X2 
                 X30 
                 X24 
                   
                   
                   
                 3.49 
                 435.55 
               
               
                 5 
                 A 
                 X2 
                 X20 
                 X24 
                 X30 
                 X24 
                 ++ 
                 + 
                 − 
                 3.88 
                 419.21 
               
               
                 6 
                 A 
                 X2 
                 X15 
                 X24 
                 X30 
                 X24 
                 ++ 
                 + 
                 − 
                 3.93 
                 433.23 
               
               
                 7 
                 E 
                 — 
                 X19 
                 X24 
                 X30 
                 X3 
                 − 
                 − 
                 − 
                 3.42 
                 405.12 
               
               
                 8 
                 E 
                 — 
                 X19 
                 X24 
                 X30 
                 X2 
                 ++ 
                 + 
                 − 
                 3.81 
                 421.17 
               
               
                 9 
                 E 
                 — 
                 X19 
                 X3 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.62 
                 405.12 
               
               
                 10 
                 E 
                 — 
                 X19 
                 X2 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 4.03 
                 421.17 
               
               
                 11 
                 A 
                 X3 
                 X19 
                 X24 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.39 
                 389.14 
               
               
                 12 
                 A 
                 X2 
                 X19 
                 X24 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 4.08 
                 405.19 
               
               
                 13 
                 B 
                 X3 
                 X19 
                 X24 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.4 
                 389.14 
               
               
                 14 
                 B 
                 X2 
                 X19 
                 X24 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.68 
                 405.19 
               
               
                 15 
                 E 
                 — 
                 X20 
                 X24 
                 X30 
                 X3 
                 − 
                 − 
                 − 
                 3.25 
                 419.13 
               
               
                 16 
                 E 
                 — 
                 X20 
                 X24 
                 X30 
                 x2 
                 + 
                 − 
                 − 
                 3.59 
                 435.19 
               
               
                 17 
                 E 
                 — 
                 X20 
                 X3 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.68 
                 419.13 
               
               
                 18 
                 E 
                 — 
                 X20 
                 X2 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 4.06 
                 435.19 
               
               
                 19 
                 A 
                 X3 
                 X20 
                 X24 
                 X30 
                 X24 
                 ++ 
                 − 
                 − 
                 3.56 
                 403.16 
               
               
                 20 
                 B 
                 X3 
                 X20 
                 X24 
                 X30 
                 X24 
                 + 
                 − 
                 − 
                 3.37 
                 403.16 
               
               
                 21 
                 B 
                 X2 
                 X20 
                 X24 
                 X30 
                 X24 
                 ++ 
                 + 
                 − 
                 3.7 
                 419.21 
               
               
                 22 
                 E 
                 — 
                 X15 
                 X24 
                 X30 
                 X3 
                 − 
                 − 
                 − 
                 3.22 
                 433.15 
               
               
                 23 
                 E 
                 — 
                 X15 
                 X24 
                 X30 
                 X2 
                 + 
                 − 
                 − 
                 3.59 
                 449.2 
               
               
                 24 
                 E 
                 — 
                 X15 
                 X3 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.7 
                 433.15 
               
               
                 25 
                 E 
                 — 
                 X15 
                 X2 
                 X30 
                 X24 
                 + 
                 − 
                 − 
                 4.06 
                 449.2 
               
               
                 26 
                 E 
                 X3 
                 X15 
                 X24 
                 X30 
                 X24 
                 ++ 
                 − 
                 − 
                 3.57 
                 417.17 
               
               
                 27 
                 B 
                 X3 
                 X15 
                 X24 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.4 
                 417.17 
               
               
                 28 
                 B 
                 X2 
                 X15 
                 X24 
                 X30 
                 X24 
                 ++ 
                 − 
                 − 
                 3.68 
                 433.23 
               
               
                 29 
                 F 
                 — 
                 X19 
                 X24 
                 X30 
                 X3 
                 − 
                 − 
                 − 
                 3.55 
                 405.12 
               
               
                 30 
                 F 
                 — 
                 X19 
                 X24 
                 X30 
                 X2 
                 + 
                 − 
                 − 
                 3.84 
                 421.17 
               
               
                 31 
                 F 
                 — 
                 X19 
                 X3 
                 X30 
                 X24 
                 + 
                 − 
                 − 
                 3.75 
                 405.12 
               
               
                 32 
                 F 
                 — 
                 X19 
                 X2 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 4.05 
                 421.17 
               
               
                 33 
                 C 
                 X3 
                 X19 
                 X24 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.38 
                 389.14 
               
               
                 34 
                 C 
                 X2 
                 X19 
                 X24 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.72 
                 405.19 
               
               
                 35 
                 D 
                 X3 
                 X19 
                 X24 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.41 
                 389.14 
               
               
                 36 
                 D 
                 X2 
                 X19 
                 X24 
                 X30 
                 X24 
                 + 
                 − 
                 − 
                 3.77 
                 405.19 
               
               
                 37 
                 F 
                 — 
                 X20 
                 X3 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.76 
                 419.13 
               
               
                 38 
                 C 
                 X3 
                 X20 
                 X24 
                 X30 
                 X24 
                 ++ 
                 + 
                 − 
                 3.33 
                 403.16 
               
               
                 39 
                 D 
                 X3 
                 X20 
                 X24 
                 X30 
                 X24 
                 ++ 
                 − 
                 − 
                 3.44 
                 403.16 
               
               
                 40 
                 D 
                 X2 
                 X20 
                 X24 
                 X30 
                 X24 
                 ++ 
                 ++ 
                 − 
                 3.8 
                 419.21 
               
               
                 41 
                 F 
                 — 
                 X15 
                 X24 
                 X30 
                 X3 
                 − 
                 − 
                 − 
                 3.51 
                 433.15 
               
               
                 42 
                 F 
                 — 
                 X15 
                 X24 
                 X30 
                 X2 
                 + 
                 − 
                 − 
                 3.81 
                 449.2 
               
               
                 43 
                 F 
                 — 
                 X15 
                 X3 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 3.66 
                 433.15 
               
               
                 44 
                 D 
                 X3 
                 X15 
                 X24 
                 X30 
                 X24 
                 ++ 
                 − 
                 − 
                 3.51 
                 417.17 
               
               
                 45 
                 D 
                 X2 
                 X15 
                 X24 
                 X30 
                 X24 
                 ++ 
                 + 
                 − 
                 3.86 
                 433.23 
               
               
                 46 
                 G 
                 — 
                 X24 
                 X3 
                 X19 
                 X30 
                 − 
                 − 
                 − 
                 3.31 
                 386.14 
               
               
                 47 
                 G 
                 — 
                 X19 
                 X2 
                 X24 
                 X30 
                 − 
                 − 
                 − 
                 3.27 
                 402.2 
               
               
                 48 
                 G 
                 — 
                 X19 
                 X24 
                 X8 
                 X30 
                 − 
                 − 
                 − 
                 2.48 
                 352.18 
               
               
                 49 
                 G 
                 — 
                 X2 
                 X24 
                 X19 
                 X30 
                 − 
                 − 
                 − 
                 3.64 
                 388.18 
               
               
                 50 
                 G 
                 — 
                 X8 
                 X24 
                 X19 
                 X30 
                 − 
                 − 
                 − 
                 2.61 
                 352.18 
               
               
                 51 
                 G 
                 — 
                 X24 
                 X3 
                 X20 
                 X30 
                 − 
                 − 
                 − 
                 3.08 
                 400.16 
               
               
                 52 
                 G 
                 — 
                 X2 
                 X24 
                 X20 
                 X30 
                 − 
                 − 
                 − 
                 3.46 
                 402.2 
               
               
                 53 
                 G 
                 — 
                 X8 
                 X24 
                 X20 
                 X30 
                 − 
                 − 
                 − 
                 2.73 
                 366.2 
               
               
                 54 
                 G 
                 — 
                 X24 
                 X3 
                 X15 
                 X30 
                 − 
                 − 
                 − 
                 3.27 
                 414.17 
               
               
                 55 
                 G 
                 — 
                 X2 
                 X24 
                 X15 
                 X30 
                 − 
                 − 
                 − 
                 3.79 
                 416.21 
               
               
                 56 
                 G 
                 — 
                 X8 
                 X24 
                 X15 
                 X30 
                 − 
                 − 
                 − 
                 2.78 
                 380.21 
               
               
                 57 
                 F 
                 — 
                 X20 
                 X2 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 4.01 
                 435.19 
               
               
                 58 
                 F 
                 — 
                 X15 
                 X2 
                 X30 
                 X24 
                 − 
                 − 
                 − 
                 4.08 
                 449.2 
               
               
                 59 
                 C 
                 X2 
                 X20 
                 X24 
                 X30 
                 X24 
                 ++ 
                 ++ 
                 + 
                 3.74 
                 419.21 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Biological activity of example 3P library 
               
             
          
           
               
                 Object 
                   
                   
                   
                   
                   
                 conc 
                 conc 
                 conc 
                 conc 
                 conc 
                 conc 
                 conc 
                 conc 
                 conc 
                   
                   
               
               
                 ID 
                 Scaffold 
                 R1 
                 R2 
                 R3 
                 R5 
                 500 
                 250 
                 50 
                 10 
                 1.0 
                 0.5 
                 0.25 
                 0.10 
                 0.001* 
                 RT 
                 M + H 
               
               
                   
               
             
          
           
               
                 60 
                 A 
                 X2 
                 X20 
                 X24 
                 X24 
                 ++ 
                 + 
                 − 
                   
                   
                   
                   
                   
                   
                 3.88 
                 419.21 
               
               
                 61 
                 B 
                 X2 
                 X20 
                 X24 
                 X24 
                 ++ 
                 + 
                 − 
                   
                   
                   
                   
                   
                   
                 3.7 
                 419.21 
               
               
                 62 
                 D 
                 X2 
                 X20 
                 X24 
                 X24 
                 ++ 
                 ++ 
                 − 
                   
                   
                   
                   
                   
                   
                 3.8 
                 419.21 
               
               
                 63 
                 C 
                 X2 
                 X20 
                 X24 
                 X24 
                 ++ 
                 ++ 
                 + 
                   
                   
                   
                   
                   
                   
                 3.72 
                 419.21 
               
               
                 64 
                 C and D 
                 X2 
                 X20 
                 X8 
                 X24 
                   
                   
                   
                 ++ 
                 ++ 
                 ++ 
                   
                 + 
                 − 
                 4.98 
               
               
                 65 
                 C and D 
                 X2 
                 X20 
                 X8 
                 X24 
                   
                   
                   
                 ++ 
                   
                   
                   
                   
                   
                 4.98 
               
               
                 66 
                 C and D 
                 X2 
                 X20 
                 X3 
                 X24 
                   
                   
                   
                 ++ 
                 ++ 
                 ++ 
                   
                 − 
                 − 
                 5.25 
               
               
                 67 
                 C and D 
                 X2 
                 X20 
                 X3 
                 X24 
                   
                   
                   
                 ++ 
                   
                   
                   
                   
                   
                 5.25 
               
               
                 68 
                 C and D 
                 X2 
                 X20 
                 X1 
                 X24 
                   
                   
                   
                 ++ 
                 ++ 
                 ++ 
                 − 
                 − 
                 − 
                 5.49 
               
               
                 69 
                 C and D 
                 X2 
                 X20 
                 X2 
                 X24 
                   
                   
                   
                 ++ 
                 ++ 
                 ++ 
                   
                 ++ 
                 + 
                 5.23 
               
               
                 70 
                 C and D 
                 X2 
                 X20 
                 X3 
                 X2 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 5.85 
               
               
                 71 
                 C and D 
                 X2 
                 X20 
                 X3 
                 X8 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 5.61 
               
               
                 72 
                 C and D 
                 X2 
                 X20 
                 X3 
                 X3 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 5.51 
               
               
                 73 
                 C and D 
                 X2 
                 X20 
                 X2 
                 X2 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 5.95 
               
               
                 74 
                 C and D 
                 X2 
                 X20 
                 X2 
                 X8 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 5.45 
               
               
                 75 
                 C and D 
                 X2 
                 X20 
                 X2 
                 X3 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 6.46 
               
               
                 76 
                 C and D 
                 X2 
                 X20 
                 X8 
                 X2 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 5.7 
               
               
                 77 
                 C and D 
                 X2 
                 X20 
                 X8 
                 X8 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 5.01 
               
               
                 78 
                 C and D 
                 X2 
                 X20 
                 X8 
                 X3 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.37 
               
               
                 79 
                 B 
                 X2 
                 X20 
                 X2 
                 X2 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 10.31 
               
               
                 80 
                 A 
                 X2 
                 X20 
                 X2 
                 X2 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 10.88 
               
               
                 81 
                 B 
                 X2 
                 X20 
                 X2 
                 X8 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 8.02 
               
               
                 82 
                 A 
                 X2 
                 X20 
                 X2 
                 X8 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 8.68 
               
               
                 83 
                 B 
                 X2 
                 X20 
                 X2 
                 X3 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 9.39 
               
               
                 84 
                 A 
                 X2 
                 X20 
                 X2 
                 X3 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 10.24 
               
               
                 85 
                 D 
                 X2 
                 X20 
                 X2 
                 X24 
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                   
                 50.92 
               
               
                 86 
                 C 
                 X2 
                 X20 
                 X2 
                 X24 
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                   
                 54.37 
               
               
                 87 
                 A or B 
                 X2 
                 X20 
                 X8 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 3.78 
                 495.59 
               
               
                 88 
                 A or B 
                 X2 
                 X20 
                 X8 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 3.86 
                 495.59 
               
               
                 89 
                 A or B 
                 X2 
                 X20 
                 X3 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 3.95 
                 530.03 
               
               
                 90 
                 A or B 
                 X2 
                 X20 
                 X3 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 3.97 
                 530.03 
               
               
                 91 
                 A or B 
                 X2 
                 X20 
                 X1 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 4.5 
                 571.69 
               
               
                 92 
                 A or B 
                 X2 
                 X20 
                 X2 
                 X24 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 4.33 
                 545.65 
               
               
                 93 
                 A and B 
                 X2 
                 X20 
                 X24 
                 X8 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 4.13 
                 495.59 
               
               
                 94 
                 A or B 
                 X2 
                 X20 
                 X24 
                 X3 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 4.33 
                 530.03 
               
               
                 95 
                 A or B 
                 X2 
                 X20 
                 X24 
                 X3 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 4.33 
                 530.03 
               
               
                 96 
                 A or B 
                 X2 
                 X20 
                 X24 
                 X1 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 4.77 
                 571.69 
               
               
                 97 
                 A and B 
                 X2 
                 X20 
                 X24 
                 X2 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 4.52 
                 545.65 
               
               
                 98 
                 A 
                 X2 
                 X20 
                 X2 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.45 
                 545.65 
               
               
                 99 
                 A 
                 X2 
                 X31 
                 X2 
                 X24 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 5.07 
                 559.67 
               
               
                 100 
                 A 
                 X2 
                 X32 
                 X2 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.05 
                 559.67 
               
               
                 101 
                 A 
                 X2 
                 X33 
                 X2 
                 X24 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 4.79 
                 557.66 
               
               
                 102 
                 A 
                 X2 
                 X34 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 6.24 
                 613.77 
               
               
                 103 
                 A 
                 X2 
                 X35 
                 X2 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.85 
                 585.71 
               
               
                 104 
                 A 
                 X2 
                 X36 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 6.33 
                 599.74 
               
               
                 105 
                 A 
                 X2 
                 X37 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 6.72 
                 599.74 
               
               
                 106 
                 A 
                 X2 
                 X45 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 4.96 
                 573.7 
               
               
                 107 
                 A 
                 X2 
                 X20 
                 X46 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 4.22 
                 530.03 
               
               
                 108 
                 A 
                 X2 
                 X20 
                 X47 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 4.87 
                 564.48 
               
               
                 109 
                 A 
                 X2 
                 X20 
                 X48 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 4.98 
                 530.03 
               
               
                 110 
                 A 
                 X2 
                 X20 
                 X49 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 4.43 
                 546.64 
               
               
                 111 
                 A 
                 X2 
                 X20 
                 X50 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 5.44 
                 552.66 
               
               
                 112 
                 A 
                 X2 
                 X20 
                 X51 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 3.78 
                 546.64 
               
               
                 113 
                 A 
                 X2 
                 X20 
                 X52 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 5.71 
                 564.48 
               
               
                 114 
                 A 
                 X2 
                 X20 
                 X9 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 5.89 
                 545.65 
               
               
                 115 
                 A 
                 X2 
                 X20 
                 X53 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.8 
                 564.48 
               
               
                 116 
                 A 
                 X2 
                 X20 
                 X54 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 4.43 
                 546.64 
               
               
                 117 
                 A 
                 X2 
                 X20 
                 X55 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 5.71 
                 564.48 
               
               
                 118 
                 A 
                 X2 
                 X20 
                 X56 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 6.9 
                 587.68 
               
               
                 119 
                 A 
                 X2 
                 X15 
                 X24 
                 X24 
                 ++ 
                 + 
                 − 
               
               
                 120 
                 A and B 
                 X2 
                 X15 
                 X8 
                 X24 
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                   
                 4.29/4.57 
               
               
                 121 
                 A and B 
                 X2 
                 X15 
                 X24 
                 X1 
                   
                   
                   
                 + 
                   
                 + 
                   
                   
                   
                 5.4 
               
               
                 122 
                 A and B 
                 X2 
                 X15 
                 X24 
                 X2 
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                   
                 5.18 
               
               
                 123 
                 A and B 
                 X2 
                 X15 
                 X24 
                 X8 
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                   
                 4.78 
               
               
                 124 
                 A and B 
                 X2 
                 X15 
                 X24 
                 X3 
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                   
                 5.07 
               
               
                 125 
                 A and B 
                 X2 
                 X15 
                 X24 
                 X4 
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                   
                 4.28 
               
               
                 126 
                 C and D 
                 X2 
                 X15 
                 X8 
                 X24 
                   
                   
                   
                 ++ 
                 + 
                 + 
                   
                 − 
                 − 
                 4.97 
               
               
                 127 
                 C and D 
                 X2 
                 X15 
                 X3 
                 X24 
                   
                   
                   
                 ++ 
                 ++ 
                 ++ 
                   
                 − 
                 − 
                 5.17 
               
               
                 128 
                 C and D 
                 X2 
                 X15 
                 X1 
                 X24 
                   
                   
                   
                 ++ 
                 + 
                 ++ 
                 − 
                 − 
                 − 
                 5.45 
                 585.71 
               
               
                 129 
                 C and D 
                 X2 
                 X15 
                 X2 
                 X24 
                   
                   
                   
                 ++ 
                 ++ 
                   
                 − 
                 + 
                 − 
                 5.18 
                 559.67 
               
               
                 130 
                 A and B 
                 X2 
                 X15 
                 X4 
                 X24 
                   
                   
                   
                 ++ 
               
               
                 131 
                 A and B 
                 X2 
                 X15 
                 X1 
                 X24 
                   
                   
                   
                 ++ 
               
               
                 132 
                 A and B 
                 X2 
                 X15 
                 X2 
                 X24 
                   
                   
                   
                 ++ 
               
               
                 133 
                 A and B 
                 X2 
                 X15 
                 X3 
                 X24 
                   
                   
                   
                 ++ 
               
               
                 134 
                 A 
                 X2 
                 X15 
                 X3 
                 X24 
                   
                   
                   
                 ++ 
                 ++ 
                 ++ 
                   
                 ++ 
                 + 
                 4.78 
               
               
                 135 
                 A 
                 X2 
                 X15 
                 X3 
                 X2 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 9.87 
               
               
                 136 
                 A 
                 X2 
                 X15 
                 X3 
                 X8 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 7.82 
               
               
                 137 
                 A 
                 X2 
                 X15 
                 X3 
                 X3 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 9.32 
               
               
                 138 
                 A 
                 X2 
                 X38 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 3.67 
                 574.69 
               
               
                 139 
                 A 
                 X2 
                 X39 
                 X2 
                 X24 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 5.07 
                 573.7 
               
               
                 140 
                 A 
                 X2 
                 X40 
                 X2 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 4.96 
                 573.7 
               
               
                 141 
                 A 
                 X2 
                 X41 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 5.16 
                 587.73 
               
               
                 142 
                 A 
                 X2 
                 X53 
                 X2 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.69/7.43 
                 599.74 
               
               
                 143 
                 A 
                 X2 
                 X42 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 5.98 
                 613.77 
               
               
                 144 
                 A 
                 X2 
                 X15 
                 X46 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 4.34 
                 544.06 
               
               
                 145 
                 A 
                 X2 
                 X15 
                 X47 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.07 
                 578.5 
               
               
                 146 
                 A 
                 X2 
                 X15 
                 X48 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                 5.05 
                 544.06 
               
               
                 147 
                 A 
                 X2 
                 X15 
                 X49 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 4.5 
                 560.66 
               
               
                 148 
                 A 
                 X2 
                 X15 
                 X50 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 5.34 
                 566.69 
               
               
                 149 
                 A 
                 X2 
                 X15 
                 X51 
                 X24 
                   
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                 3.95 
                 560.66 
               
               
                 150 
                 A 
                 X2 
                 X15 
                 X52 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 5.78 
                 578.5 
               
               
                 151 
                 A 
                 X2 
                 X15 
                 X9 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.78 
                 559.67 
               
               
                 152 
                 A 
                 X2 
                 X15 
                 X53 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 + 
                   
                   
                 5.97 
                 578.5 
               
               
                 153 
                 A 
                 X2 
                 X15 
                 X54 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 4.32 
                 560.66 
               
               
                 154 
                 A 
                 X2 
                 X15 
                 X55 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 5.88 
                 578.5 
               
               
                 155 
                 A 
                 X2 
                 X15 
                 X56 
                 X24 
                   
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                 7.25 
                 601.71 
               
               
                 156 
                 A 
                 X3 
                 X19 
                 X24 
                 X24 
                 − 
                 − 
                 − 
                   
                   
                   
                   
                   
                   
                 3.39 
                 389.14 
               
               
                 157 
                 B 
                 X3 
                 X19 
                 X24 
                 X24 
                 − 
                 − 
                 − 
               
               
                 158 
                 C 
                 X3 
                 X19 
                 X24 
                 X24 
                 − 
                 − 
                 − 
                   
                   
                   
                   
                   
                   
                 3.38 
                 389.14 
               
               
                 159 
                 D 
                 X3 
                 X19 
                 X24 
                 X24 
                 − 
                 − 
                 − 
               
               
                 160 
                 C and D 
                 X3 
                 X19 
                 X8 
                 X24 
                   
                   
                   
                 − 
                 − 
                 − 
                   
                 − 
                 − 
                 4.8 
               
               
                 161 
                 C and D 
                 X3 
                 X19 
                 X3 
                 X24 
                   
                   
                   
                 ++ 
                 − 
                 − 
                   
                 − 
                 − 
                 5.14 
               
               
                 162 
                 C and D 
                 X3 
                 X19 
                 X1 
                 X24 
                   
                   
                   
                 + 
                 − 
                 − 
                 − 
                 − 
                 − 
                 5.45 
                 542.04 
               
               
                 163 
                 C and D 
                 X3 
                 X19 
                 X2 
                 X24 
                   
                   
                   
                 ++ 
                 − 
                 − 
                   
                 − 
                 − 
                 5.2 
               
               
                 164 
                 C and D 
                 X3 
                 X43 
                 X24 
                 X2 
                   
                   
                   
                 + 
                   
                 − 
                   
                   
                   
                 3.45 
               
               
                 165 
                 C and D 
                 X3 
                 X44 
                 X24 
                 X2 
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                   
                 4 
               
               
                 166 
                 A and B 
                 X3 
                 X43 
                 X24 
                 X2 
                   
                   
                   
                 ++ 
                   
                 − 
                   
                   
                   
                 3.59 
               
               
                 167 
                 A and B 
                 X3 
                 X44 
                 X24 
                 X2 
                   
                   
                   
                 ++ 
                   
                 ++ 
                   
                   
                   
                 3.97 
               
               
                 168 
                 A or B 
                 X3 
                 X19 
                 X8 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
               
               
                 169 
                 A or B 
                 X3 
                 X19 
                 X8 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
               
               
                 170 
                 A or B 
                 X3 
                 X19 
                 X3 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
               
               
                 171 
                 A or B 
                 X3 
                 X19 
                 X3 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
               
               
                 172 
                 A or B 
                 X3 
                 X19 
                 X1 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
               
               
                 173 
                 A and B 
                 X3 
                 X19 
                 X1 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
               
               
                 174 
                 A and B 
                 X3 
                 X19 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
               
               
                 175 
                 A and B 
                 X3 
                 X19 
                 X2 
                 X24 
                   
                   
                   
                   
                 − 
                   
                 − 
               
               
                 176 
                 A and B 
                 X3 
                 X19 
                 X24 
                 X8 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 4.88/5.61 
                 465.95 
               
               
                 177 
                 A and B 
                 X3 
                 X19 
                 X24 
                 X3 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 6.06/6.52 
                 500.39 
               
               
                 178 
                 A and B 
                 X3 
                 X19 
                 X24 
                 X1 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 9.09 
                 542.04 
               
               
                 179 
                 A and B 
                 X3 
                 X19 
                 X24 
                 X2 
                   
                   
                   
                   
                 − 
                   
                 − 
                   
                   
                 7.43 
                 516.01 
               
               
                   
               
             
          
         
       
     
       FIG. 1: Sidearms for Tables 1 and 2 
       [0110]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0111]    Throughout the specification and the claims (if present), unless the context requires otherwise, the term “comprise”, or variations such as “comprises” or “comprising”, will be understood to apply the inclusion of the stated integer or group of integers but not the exclusion of any other integer or group of integers. 
         [0112]    Throughout the specification and claims (if present), unless the context requires otherwise, the term “substantially” or “about” will be understood to not be limited to the value for the range qualified by the terms. 
         [0113]    It should be appreciated that various other changes and modifications can be made to any embodiment described without departing from the spirit and scope of the invention. 
       REFERENCES 
       [0000]    
       
         [1] Patel, Y. C. (1999) Somatostatin and its receptor family.  Front. Neuroendocr.  20, 157-198 
         [2] Csaba, Z. and Doumaud, P. (2001) Cellular biology of somatostatin receptors.  Neuropeptides  35, 1-23 
         [3] T Reisine, T. (1995) Somatostatin receptors;  Am. J. Pysiol . ( Gastrointest. Liver Physiol.  32) 269, G813-G820 
         [4] Bauer, W. et al. (1982) SMS201-995: A very potent and selective octapeptide analogue of somatostatin with prolonged action.  Life Sci.  31, 1133-1140 
         [5] Lamberts, S. W. J. et al. (1996) Drug therapy: Octreotide.  N. Eng. J. Med.  334, 246-254 
         [6] Robinson, C. and Castaner, J. (1994) Lanreotide acetate.  Drugs Future  19, 992-999 
         [7] Reisine, T. and Bell. G. I. (1995) Molecular biology of somatostatin receptors.  Endocr. Rev.  16, 427-442