Synthesis and Biological Studies of a Novel CB1 Antagonist^[*]

Abstract

This paper describes the synthesis, early process development, salt selection strategies and pre clinical evaluation of novel, potent and selective CB1 antagonist, 8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide 1. The CB1 antagonism of compound 1 is also confirmed by reversal of CB1 agonist-induced hypothermia in Swiss albino mice. The process for the preparation of the compound 1 as a crystalline solid is also described. The crystalline form of the compound is found to be low bioavailable, therefore attempts have been made to improve its bioavailability through polymorphic transformation and salt formation. None of the salts prepared were found to be suitable for further development. The amorphous form of the compound 1 is found to be better suited. In vivo efficacy study of the amorphous form of compound 1 in 5% sucrose solution intake model in female Zucker fa/fa rats at single oral dose of 10 mg/kg demonstrates better reduction in the sucrose solution consumption than the corresponding crystalline form. The plasma concentration C_max at AUC exposure of the amorphous form of the compound 1 is significantly improved and better than the C_max of the corresponding crystalline form of the compound 1. On the basis of the efficacy, pharmacokinetic and toxicological evaluations, the compound 1 in the amorphous form is selected as a pre-clinical lead candidate.

Key words

cannabinoid CB1 and CB2 receptors - neutral antagonists - anti-obesity drugs - piperidin-1-ylamide derivatives

^* ZRC communication 465

• References

• 1 https://apps.who.int/infobase/Publicfiles/SuRF2.pdf
• 2 Bray GA. Obesity: The Disease. J Med Chem 2006; 49: 4001-4007
• 3 http://www.who.int/gho/ncd/risk_factors/obesity_text/en/
• 4 Swinburn BA, Sacks G, Hall KD et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet 2011; 378: 804-814
• 5 Kopelman PG. Obesity as a medical problem. Nature 2000; 404: 635-643
• 6 Flegal KM, Graubard BI, Williamson DF et al. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA 2007; 298: 2028-2037
• 7 Dansinger ML, Gleason JA, Griffith JL et al. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease reduction: a randomised trial. JAMA 2005; 293: 43-53
• 8 LeBlanc ES, O’Connor E, Wtitlock PD et al. Effectiveness of primary care – relevant treatments for obesity in adults: a systematic evidence review for the U. S. Preventive Services Task Force. Ann Int Med 2011; 155: 434-447
• 9 Wing RR, Tate DF, Gorin AA et al. A self-regulation program for maintenance of weight loss. N Eng J Med 2006; 355: 1563-1571
• 10 Harrold J, Pinkney J, Wiliams G. Control of obesity through the regulation of appetite. Drug Discov Today: Ther Strat 2004; 1: 219-225
• 11 Kirkham TC. Cannabinoids and appetite: food craving and food pleasure. Int Rev Psychiat 2009; 21: 163-171
• 12 Kirkham TC, Williams CM. Endogenous cannabinoids and appetite. Nut Res Rev 2001; 14: 65-86
• 13 Bosier B, Muccioli GG, Hermans E et al. Functionally selective cannabinoid receptor signalling: Therapeutic implications and opportunities. Biochemical Pharmacology 2010; 80: 1-12
• 14 Sorbera LA, Castaner J, Silvestre JS. Rimonabant Hydrochloride. Drugs Future 2005; 30: 128-137
• 15 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500014774.pdf
• 16 Plieth J. Obesity: what next after the CB1 antagonists’ failure. Scrip 2008; 44-47
• 17 Hertzog DL. Recent advances in the cannabinoids. Expert Opin Ther Patents 2004; 14: 1435-1452
• 18 Lange JHM, Kruse CG. Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists. Drug Discov Today 2005; 10: 693-702
• 19 Muccioli GG, Lambert DM. Current Knowledge on the Antagonists and Inverse Agonists of Cannabinoid Receptors. Curr Med Chem 2005; 12: 1361-1394
• 20 Lange JHM, Coolen HKAC, van Stuivenberg HH et al. Synthesis, Biological Properties, and Molecular Modeling Investigations of Novel 3,4-Diarylpyrazolines as Potent and Selective CB1 Cannabinoid Receptor Antagonists. J Med Chem 2004; 47: 627-643
• 21 Need AB, Davis RJ, Alexander-Chacko JT et al. The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats. Psychopharmacology 2006; 184: 26-35
• 22 Ruiu S, Pinna GA, Marchese G et al. Synthesis and Characterization of NESS 0327: A Novel Putative Antagonist of the CB1 Cannabinoid Receptor. J Pharmacol Exp Ther 2003; 306: 363-370
• 23 Stoit AR, Lange JHM, den Hartog AP et al. Design, Synthesis and Biological Activity of Rigid Cannabinoid CB1 Receptor Antagonists. Chem Pharm Bull 2002; 50: 1109-1113
• 24 Makriyannis A. Should peripheral CB1 cannabinoid receptors be selectively targeted for therapeutic gain?. Trends Pharmacol Sci 2008; 30: 1-7
• 25 Bermudez-Silva FJ, Viveros MP, McPartland JM et al. The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning?. Pharmacol Biochem Behav 2010; 95: 375-382
• 26 Cluny NL, Chambers AP, Vemuri VK et al. The neutral cannabinoid CB1 receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat. Pharmacol Biochem Behav 2011; 97: 537-543
• 27 Xie Y, Zheng Z, Li S et al. Novel selective antagonist of the cannabinoid CB1 receptor, MJ15, with prominent anti-obesity effect in rodent models. Eur J Pharmacol 2010; 637: 178-185
• 28 Lohray BB, Lohray VB, Srivastava BK. WO Patent 2006/025069, 2006. Chem Abstr 2006; 144: 292751
• 29 Weng Y, Sun S, Park J et al. Cannabinoid 1 (CB1) receptor mediates WIN55, 212-2 induced hypothermia and improved survival in a rat post-cardiac arrest model. Resuscitation 2012; 83: 1145-1151
• 30 U.S. Environmental Protection Agency . Integrated Risk Information System (IRIS) on N,N-Dimethyl formamide. National Center for Environmental Assessment, Office of Research and Development; Washington, DC: 1999
• 31 Rinaldi-Carmona M, Le Duigou A, Oustric D et al. Pharmacol Exp Ther 1998; 287: 1038