Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies (2011)

The endogenous cannabinoid (eCB) system plays a significant role in appetitive drive and feeding behavior. Therefore, antagonism of this receptor-mediated system was predicted to provide therapeutic benefit for the treatment of disorders associated with excess appetitive drive, such as obesity and substance abuse, as well as other disorders (1,2,3). Toward this end, cannabinoid receptor antagonists have been designed and investigated as pharmacotherapeutic agents. Rimonabant was the first-in-class of such compounds. Its biological activity is thought to be mediated by CB1 (cannabinoid receptor subtype 1) antagonist or inverse-agonist action, i.e., it acts as a functional antagonist in vivo. Rimonabant suppresses feeding in laboratory animals (4,5,6) and also shows efficacy at reducing body weight and improving cardiovascular and metabolic risk factors in nondiabetic and diabetic overweight and obese patients (7,8,9,10). However, concerns over psychiatric adverse effects such as depression, anxiety, and suicidal ideations, and other adverse effects (e.g., increased incidence of nausea, vomiting, and pruritis) led to the withdrawal of rimonabant from the market worldwide. The experience with rimonabant prompted the questioning of the CB1 antagonism approach. However, concern has now been expressed that the experience with one or two drugs might have potentially led to premature abandonment of an entire mechanism—a mechanism that might be valuable for treatment of several disorders that currently lack effective therapy (11,12,13,14). That is, the observed adverse effects might be related to the individual drug (a drug effect) rather than the mechanism of action (a class effect). Therefore, further understanding of the behavioral pharmacological, neurochemical, and cellular effects of rimonabant and of more recent novel CB1 receptor antagonists might shed some light on the therapeutic potential of such compounds. Specifically, (i) potential efficacy of peripherally restricted CB1 antagonists for obesity and type 2 diabetes and other disorders, (ii) the effects of CB1 neutral antagonists, as opposed to inverse agonists, on weight and mood disorders, (iii) the extent and mechanism(s) by which central CB1 receptor antagonism produces global effects on anhedonia or depressed mood, and (iv) whether combining lower doses of these agents with agents from other drug classes could improve or maintain efficacy while lessening adverse effects (see also Table 1 for a summary of points 1–3). The eCB system (AKA endocannabinoid) was identified in the early 1990s during investigations into the mechanism of action of Delta(9)-tetrahydrocannabinol, the major psychoactive chemical component in Cannabis sativa (15,16). The cloning of cannabinoid receptors led to the identification of endogenous molecules capable of binding and activating them, defined as “endocannabinoids” because of their affinity to Delta(9)-tetrahydrocannabinol binding sites (17). Demonstrated or putative eCBs include anandamide (arachidonoylethanolamide (18)), 2-arachidonoyl glycerol (19,20), and several others (e.g., refs. 21,22,23,24). The endocannabinoids are generated on an as-needed basis (25,26,27,28,29) and are released postsynaptically to travel retrogradely and bind to presynaptic receptors (30,31,32). Both 2-arachidonoyl glycerol and arachidonoylethanolamide have been found in blood plasma, brain, heart, gut, liver, pancreas, muscle, adipose tissue, kidney, testis, skin, spleen, uterus and skeleton, suggesting that they regulate a wide range of effects through the activation of the cannabinoid receptors present in such tissues. There are two main cannabinoid receptor types, termed CB1 and CB2, both of which are seven-transmembrane (7TM) G protein–coupled receptors. In human, CB1 is found ubiquitously but is preferentially localized in the brain and the spinal cord (33). Indeed, CB1 receptors are one of the most abundant G protein–coupled receptors located within the mammalian brain and are present in highest concentration in olfactory and cortical brain regions (neocortex and pyriform cortex), hippocampus, amygdala, basal ganglia, thalamic and hypothalamic nuclei, cerebellar cortex, and brainstem nuclei (34,35). These central CB1 receptors had previously been most widely studied, as it was presumed that they were the key target underlying rimonabant's antiobesity effects. However, a wealth of more recent evidence has clearly demonstrated the pivotal role that peripheral CB1 receptors play in energy homeostasis in sites such as the gastrointestinal tract, liver, pancreas, skeletal muscle, and adipocytes (see refs. 36,37 for review). Rimonabant (N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide (38)) was approved in the European Union for the treatment of obesity (defined as BMI ≥30 kg/m2) or for patients with BMI >27 kg/m2 plus associated risk factors (such as type 2 diabetes or dyslipidemia). It was denied approval by the US Food and Drug Administration due to adverse psychiatric side effects (39) and was subsequently withdrawn from the other markets. Shortly after the European Medicines Agency called for withdrawal of rimonabant from the market in 2008, several pharmaceutical companies (i.e., Merck (Whitehouse Station, NJ), Pfizer (New York, NY), Sanofi-aventis (Paris, France), Solvay (Brussels, Belgium) announced that they would stop further clinical research on this class of drug. However, medicinal chemistry teams within other companies and academia have continued to synthesize novel CB1 receptor antagonists, largely in an effort to generate: peripherally restricted compounds; “neutral” or “pure” antagonists; or compounds having both features. The following is a brief summary of some of the most well-characterized of these alternate CB1 antagonists. Taranabant (MK-0364), N-[(1S,2S)-3- (4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{(5-(trifluoromethyl)pyridin-2-yl)oxy}propanamide (40) was discovered at Merck starting from a high throughput screening lead. It is a cyclic amide analog of the lead compound for oral efficacy and minimized production of reactive metabolites. Mutagenesis and computer-simulated docking studies (41) suggest that taranabant binds to the same general area of the CB1 receptor as does rimonabant, but with some differences, notably that taranabant hydrogen bonds with S(7.39)383 but not K(3.28)192, whereas the opposite is true for rimonabant. This difference is the presumptive explanation for taranabant's higher affinity for the CB1 receptor. Taranabant acts as an inverse agonist and inhibits food intake and weight gain and reduces body weight correlated with brain CB1 receptor occupancy (42). In addition, mechanism-of-action studies have strongly suggested that taranabant's weight loss effects are at least in large part due to increases in energy expenditure and fat oxidation (43). In low-dose (44) and high-dose (45) phase 3 clinical trial studies, taranabant produced statistically significant incidences of psychiatric-related adverse experiences. Otenabant (CP-945,598), 1-[9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H- purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide, was discovered at Pfizer as part of an effort to design conformationallyrestricted analogs of the bioactive conformation of the diarylpyrazole rimonabant (46). It was hypothesized that the low-energy conformation and hydrogen bonding of the amide carbonyl of rimonabant could be mimicked by a purine. It was also desired to achieve good central nervous system penetration and minimize production of reactive metabolites. Otenabant displays high (sub nmol/l) affinity for human CB1 receptors vs. CB2 receptors (>10,000 lower affinity) and antagonizes cannabinoid agonist-induced effects in vivo. It inhibits food intake and stimulates energy expenditure (47) and had reached phase 3 clinical trials before its withdrawal from development. Surinabant (SR147778), 5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide, from Sanofi-Synthelabo (Paris, France), is a CB1 receptor antagonist that has high (sub nmol/l) affinity for human CB1 recombinant receptors, much lower affinity (>100-fold) for CB2 receptors and is inactive at other receptor, enzyme, or ion channel targets (48). It is orally active and reduces ethanol or sucrose consumption in mice and rats and it reduces food intake in fasted and in nonfasted rats (48). Surinabant reached phase 2 clinical trials before its withdrawal from development. Ibipinabant (SLV-319), 4S-(–)-3-(4-Chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine, was synthesized at Zydus based on structural similarity to rimonabant. The design was based on the bioisosteric replacement of rimonabant's pyrazole moiety with dihydropyrazole(49). N-aminomorpholine was the optimal side chain and the bisulfate salt was best for bioavailability. Computer modeling was consistent with docking of the ligand to the CB1 receptor. Oral efficacy was demonstrated by inhibition of sucrose intake in fasted female Zucker fa/fa rats. Bioisosteric replacement of the dihydropyrazole nucleus of SLV-319 by either imidazole or oxazole results in loss of required CB1 receptor binding conformation and pharmacologic effect as a CB1 receptor antagonist (50). Prior to its withdrawal from development, Ibipinabant reached phase 2 clinical trials. TM38837 is a first-in-class second generation CB1 antagonist derived from 7TM Pharma's discovery program targeting the development of CB1 receptor antagonists acting specifically in the periphery. Although the structure of TM38837 has not been published, it is likely similar to those described in 7TM Pharma patents based on the structure of rimonabant. Most recently, the company announced that a phase 1 clinical trial confirmed TM38837 is restricted to the periphery of the human body. The double-blind placebo controlled crossover phase 1 clinical trial assessed the ability of TM38837 to attenuate the centrally mediated side effects of Delta(9)-tetrahydrocannabinol (51). Mild abdominal discomfort such as nausea and diarrhea was reported in <10% of the subjects receiving the drug. 7TM researchers had previously reported at the 2010 International Obesity Conference in Stockholm that TM38837 decreases body weight comparable to rimonabant in rodents, but does not reach the brain in significant levels. In addition, they report that TM38837 is devoid of a range of behavioral effects indicative of activity at brain CB1 receptors (52). AM4113 (N-piperidin-1-yl-2,4-dichlorophenyl-1H-pyrazole-3-carboxamide analog) is a pyrazole analog structurally related to rimonabant, synthesized at the Center for Drug Discovery, Northeastern University (Boston, MA), in the laboratory of Alexander Makriyannis. AM4113 is a putative neutral antagonist that suppresses food intake and food-reinforced behavior, but unlike rimonabant does not induce signs of nausea in rats (53). AM6545, [5-(4-[4-cyanobut-1-ynyl]phenyl)-1-(2,4-dichlorophenyl)- 4-methyl-N-(1,1-dioxo-thiomorpholino)-1H-pyrazole-3-carboxamide], is a peripherally restricted, less lipid soluble analog of rimonabant that retains high affinity and selectivity for the CB1 receptor. In radioligand displacement assays, AM6545 has a KI of 3.3 nmol/l for CB1 receptor, which is similar to that of rimonabant, and >100-fold CB1/CB2 selectivity (54). It is also synthesized at the Center for Drug Discovery, Northeastern University, in the laboratory of Alexander Makriyannis. Following acute parenteral or oral administration, a brain to plasma concentration ratio of 0.03 was reported, as compared with a ratio of 0.8 for rimonabant. AM6545 can also be classified as a neutral antagonist as it does not reduce GTPγs binding in mouse brain. AM6545 improves the metabolic profile in mice with diet-induced obesity but was reported to be inactive in a range of behavioral paradigms that measure activity at brain CB1 receptors (54,55). However, AM6545 does reduce food-reinforced operant responding and intake of and vs. its to the periphery. a peripherally restricted CB1 is an analog of rimonabant. It has affinity for the CB1 receptor and selectivity over the CB2 receptor It suppresses food intake and body weight gain in rats It has a concentration ratio in rats and it similar in food intake and body weight gain in CB1 receptor mice as in mice suggesting that the effect might not be mediated by the CB1 receptor. from of a a to the on the of rimonabant. It food intake and body weight gain in mice It that acts at peripheral CB1 receptors. It is that this selectivity is as a of high by or by by in a putative neutral CB1 is a analog of the cannabinoid It reduces food consumption and body weight of rats of these results is by the that the compound also consumption it might reduce in general of and activity this was not for the in It is also not whether the compound some a structural of novel having CB1 receptor antagonist activity was reported by The compounds are synthesized by the of a for the in an that the bioactive These compounds reduce the body weight of diet-induced obese an effect that after a The effect of these compounds is to be due to Although it is well that rimonabant central CB1 receptors that and to in food its effects on peripheral to increased energy expenditure are now also well Specifically, at the fat lipid and have been rimonabant's effects could be due to (i) action on brain CB1 receptors that through the nervous (ii) action on peripheral CB1 receptors expressed on or skeletal muscle, or (iii) action on both brain and peripheral receptors. that mice the CB1 receptor receptor less fat and higher energy expenditure than suggesting a role for CB1 receptors in suggested that rimonabant's efficacy a metabolic because the body weight loss in mice was higher than in mice during a as well as in a investigated at the and in of adipose in diet-induced obese rats. reported that in obesity was with a of similar to rats and a in by In and obese Zucker rimonabant produced to its effect while to body weight The role of the system on the of has been by the of CB1 receptors in adipose and these results strongly suggest a peripheral component to the effect of rimonabant. the of antagonism of central vs. peripheral CB1 receptors in effects of rimonabant has not been These suggest that the of peripherally restricted CB1 antagonists lead to compounds that maintain efficacy at weight loss while devoid of adverse central nervous system effects. but of studies have now behavioral effects of putative CB1 receptor antagonists, but most of these compounds have either not been demonstrated to lack effects on central CB1 receptors (e.g., have been suggested to include (e.g., or the results energy or weight loss have not been (e.g., recent be the compound AM6545 and the phase 1 clinical trial compound TM38837 (see AM6545 to have an profile of peripheral loss of body and of metabolic profile of body weight (54). most and is the that this putative peripherally restricted drug efficacy at for in to its metabolic effects 7TM Pharma had reported in that its first-in-class second generation CB1 antagonist TM38837 shows efficacy in of obesity and type 2 diabetes and shows to the periphery in In addition, 7TM most reported that TM38837 was at central nervous effects of Delta(9)-tetrahydrocannabinol in phase 1 clinical trial with subjects (51). recent evidence also that CB1 antagonist effects on body weight as either central of or peripheral of energy expenditure is In an to CB1 receptors in energy mice central CB1 receptors in the and nucleus of the while CB1 on peripheral were and These CB1 mice a and to diet-induced obesity that to as a of nervous system activity and a in energy suggesting that CB1 specifically be in obesity in patients with be to the extent to which peripherally restricted CB1 receptor antagonists, devoid of the central nervous system adverse can also this system to in a effective The of the that rimonabant as an inverse agonist in and in vivo. However, it is less to extent this action at the CB1 receptor is for its effects or to extent this action to its adverse effects. to the of chemical bonding to a receptor affinity) and activation of some mechanism inverse to activation of a receptor that produces an effect opposite of for that and neutral antagonism to binding to a receptor that does not activation of a to in basal Although putative neutral CB1 receptor antagonists have been (e.g., AM6545, and the of CB1 receptor antagonists, rimonabant and as inverse agonists, activity and effects that are opposite in from those produced by eCB at these receptors. Rimonabant has much affinity for CB1 than for CB2 receptors in the nmol/l range vs. (38)) and has significant affinity for other receptor such as or or or It the Rimonabant inhibits to of in which is to be suggesting activity at Rimonabant can induce and food consumption in several of these effects are opposite to those produced by CB1 receptor However, several inverse effects could from true neutral antagonism at CB1 receptors that are basal activation from endogenous endocannabinoids such as anandamide and 2-arachidonoyl this is the neutral CB1 receptor antagonists might as inverse in vivo. It is also that compounds such as rimonabant the of active CB1 receptors are active in the of endogenous antagonists, in this would not the of active receptors. rimonabant's at and body weight is a of endogenous receptor activation or by its activity is a of studies assessed the effect of a CB1 receptor neutral antagonist on these However, with the of rimonabant and the related taranabant in the studies of the behavioral pharmacologic effects of putative neutral antagonists have It is to whether these compounds their effects of feeding and weight loss while a incidence of adverse The neutral antagonist was reported to consumption in animals and reduce food intake and weight gain in Zucker rats suggesting that neutral antagonism of the CB1 receptor can attenuate feeding and also increases energy not activity or induce and at effects reported following to high doses of rimonabant in rats. was not associated with behavior. However, has lower than rimonabant, the lack of these effects might be by its to the periphery rather than to its lack of inverse-agonist In the putative food consumption in rats suggesting that CB1 antagonism can feeding by eCB rather than by activity at CB1 receptors. have demonstrated that the CB1 AM4113 reduces food intake and produces weight loss treatment with AM4113 also be devoid of some adverse effects associated with rimonabant. AM4113 signs of nausea in rats does it the of a However, AM4113 produces effects similar to that with rimonabant in an recently, a novel class of CB1 receptor have efficacy at reducing food intake but the adverse effect profile is currently is as to whether it is for a ligand to as a true neutral antagonist in a system and those in this as it to CB1 receptor antagonists It can be that an effective for a by drive the while other the treatment of or disorders target excess while food as well as regulate the of food other by a general large of laboratory suggest that the CB1 antagonist rimonabant not decreases for both and but also for several classes of while both obesity and researchers in CB1 antagonists for of excess food or drug the extent to which these agents attenuate appetitive a global studies have whether CB1 receptor antagonism excess food consumption by have assessed the effect of these agents on feeding in rimonabant and similar antagonists attenuate feeding in but can also effects in rimonabant decreases feeding in mice by but also decreases for food in mice rimonabant reduces food intake in obese and Zucker but the effect is in obese animals In addition, while some suggest that rimonabant preferentially the of other suggest that consumption of high high and is by a CB1 antagonist Most recently, have observed that rimonabant is as effective at for in mice as it is at for in mice the to gain to either is However, the is rimonabant is at operant responding for but is effective at is a by an to experience in In laboratory anhedonia is widely identified by a in consumption of a The that CB1 antagonists at a wide range of food and drug that CB1 receptor antagonists the of this could the and of these drugs in this other studies that some or following CB1 receptor In the of anhedonia in for treatment with rimonabant the sucrose consumption by to suggesting that CB1 antagonists be a have reported that rimonabant to attenuate effects in rats rimonabant more operant Following a similar rimonabant decreases higher ratio but does not attenuate responding at a ratio while rimonabant by several drugs rimonabant to an on its and has been reported to induce a but from food and drug the are of studies the effect of rimonabant treatment on other such as novel or a recent demonstrated that the CB1 agonist increased and in female suggesting that CB1 antagonists might as a treatment for with The over rimonabant's efficacy at reducing weight was in by the concern the of CB1 receptor antagonists because of increased of depression, anxiety, and suicidal related to their These concerns led the European Medicines Agency in to of of rimonabant in the European it had been by Rimonabant was withdrawn from the European Union by the because clinical was not following to its i.e., were it to patients at high risk for of or have on the acute CB1 antagonist treatment produces either or effects and these effects not the or CB1 receptor inverse produces effect on in rats but an profile in mice reported that with rimonabant produced effects in rats in the This a further and investigated for production of psychiatric adverse effects with rimonabant for that rats had of in and in and in for therapy for obesity is from the treatment of which from agents to of drugs that of blood agents to be a to of obesity in to improve efficacy while and adverse effects. drug of currently or was from the market approved drugs have efficacy for reducing body and and and and with and several others are at of clinical (see for review). The CB1 receptor system has been demonstrated to with several other and Most the receptor system plays an role in Both and induce and the is one of two currently US Food and Drug drugs for treatment of overweight and obesity of its in the European Union due to adverse cardiovascular The not approved for treatment of are for this in patients for Specifically, the receptor is the most widely receptor subtype in the of and weight loss The agonist the most antiobesity drug for several to produces in and body weight that have been to its high affinity for receptors acting receptor are currently in of clinical trials. The of a CB1 antagonist with a agonist would to potential as an antiobesity the of required to be effective and potentially improving the therapeutic this rimonabant or the receptor agonist and in to both agents for by operant responding a ratio of in rimonabant produced a in for the food This is by other that of CB1 receptors can within the system compared to The benefit of compounds for overweight and obesity is their The receptor system plays a role in and during the have the most effects of CB1 in rats have been to with the system as previously rimonabant associated with a in rats was associated with of in as well as It is to that of is to to the therapeutic effects of Most demonstrated that doses of rimonabant and which had effect on in a effect the and of drugs with of action, it is not that the of individual compounds questioning of the approach. This has been the for functional antagonism of the CB1 receptor. However, several suggest that abandonment of the CB1 might be in design and of novel compounds with chemical and results drug from on the of to the behavioral effects of second generation CB1 antagonists, is for peripherally restricted CB1 antagonists, the recent effects of AM6545 and the and clinical effects of TM38837 This was by of and of University of The of