Discovery of 1-(2,4-Dichlorophenyl)- N -(piperidin-1-yl)-4-((pyrrolidine-1- sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1 H -pyrazole-3-carboxamide as a novel peripherally restricted cannabinoid-1 receptor antagonist with significant weight-loss efficacy in diet-induced obese mice

Journal of Medicinal Chemistry

Volumn 56, Issue 24, 2013, Pages 9920-9933

  Chang, Chun Ping ^a   Wu, Chien Huang ^a   Song, Jen Shin ^a   Chou, Ming Chen ^a   Wong, Ying Chieh ^a   Lin, Yinchiu ^a   Yeh, Teng Kuang ^a   Sadani, Amit A ^a   Ou, Ming Hung ^a   Chen, Kun Hung ^a   Chen, Pei Hsuan ^a   Kuo, Po Chu ^a   Tseng, Chen Tso ^a   Chang, Kuei Hua ^a   Tseng, Shi Liang ^a   Chao, Yu Sheng ^a   Hung, Ming Shiu ^a   Shia, Kak Shan ^a  

^a NATIONAL HEALTH RESEARCH INSTITUTES   (Taiwan)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2,4 DICHLOROPHENYL) N (PIPERIDIN 1 YL) 4 [(PYRROLIDINE 1 SULFONAMIDO)METHYL] 5 [5 [[4 (TRIFLUOROMETHYL)PHENYL]ETHYNYL]THIOPHENE 2 YL] 1H PYRAZOLE 3 CARBOXAMIDE; ANTIOBESITY AGENT; CANNABINOID 1 RECEPTOR ANTAGONIST; PYRAZOLE; SULFANILAMIDE; SULFONAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG BRAIN LEVEL; DRUG DESIGN; DRUG EFFICACY; DRUG STRUCTURE; DRUG SYNTHESIS; MOUSE; NONHUMAN; OBESITY; STRUCTURE ACTIVITY RELATION; WEIGHT REDUCTION;

EID: 84891281974     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401158e     Document Type: Article

References (50)

1. Wilson, R. I.; Nicoll, R. A. Endocannabinoid signaling in the brain Science 2002, 296, 678-682
2. Howleff, A. C.; Barth, F.; Bonner, T. I.; Cabral, G.; Casellas, P.; Devane, W. A.; Felder, C. C.; Herkenham, M.; Mackie, K.; Martin, B. R.; Mechoulam, R.; Pertwee, R. G. International union of pharmacology XXVII. Classification of cannabinoid receptors Pharmacol. Rev. 2002, 54, 161-202
3. Carrier, E. J.; Kearn, C. S.; Barkmeier, A. J.; Breese, N. M.; Yang, W.; Nithipatikom, K.; Pfister, S. L.; Campbell, W. B.; Hillard, C. J. Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism Mol. Pharmacol. 2004, 65, 999-1007
4. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids Nature 1993, 365, 61-65
5. 1 receptor blockade in the treatment of visceral obesity and its cardiometabolic complications Br. J. Pharmacol. 2011, 163, 1423-1431
6. Janero, D. R.; Lindsley, L.; Vemuri, V. K.; Makriyannis, A. Cannabinoid 1 G protein-coupled receptor (periphero-)neutral antagonists: emerging therapeutics for treating obesity-driven metabolic disease and reducing cardiovascular risk Expert Opin. Drug Discovery 2011, 6, 995-1025
7. Jourdan, T.; Godlewski, G.; Cinar, R.; Bertola, A.; Szanda, G.; Liu, J.; Tam, J.; Han, T.; Mukhopadhyay, B.; Skarulis, M. C.; Ju, C.; Aouadi, M.; Czech, M. P.; Kunos, G. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes Nat. Med. 2013, 1132-1140
8. Tam, J.; Vemuri, V. K.; Liu, J.; Bátkai, S.; Mukhopadhyay, B.; Godlewski, G.; Osei-Hyiaman, D.; Ohnuma, S.; Ambudkar, S. V.; Pickel, J.; Makriyannis, A.; Kunos, G. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity J. Clin. Invest. 2010, 120, 2953-2966
9. 7TM Pharma completed a phase I clinical trial and confirmed that TM38837 is restricted to the periphery in humans (http://www.7tm.com/News.aspx?M= News&PID=42&NewsID=58, news release November 11, 2010).
10. Klumpers, L. E.; Fridberg, M.; de Kam, M. L.; Little, P. B.; Jensen, N. O.; Kleinloog, H. D.; Elling, C. E.; van Gerven, J. M. Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects. Br. J. Clin. Pharmacol. 2013, doi: 10.1111/bcp.12141.
11. Chorvat, R. J. Peripherally restricted CB1 receptor blockers Bioorg. Med. Chem. Lett. 2013, 23, 4751-4760
12. Kenkre, J.; Tan, T.; Bloom, S. Treating the obese diabetic Expert Rev. Clin. Pharmacol. 2013, 6, 171-183
13. Bays, H.; Dujovne, C. Pharmacotherapy of obesity: Currently marketed and upcoming agents Am. J. Cardiovasc. Drugs 2002, 2, 245-253
14. Kaya, A.; Aydin, N.; Topseverm, P.; Filiz, M.; Oztürk, A.; DagÌar, A.; Kilinç, E.; Ekmekcioglu, C. Efficacy of sibutramine, orlistat and combination therapy on short-term weight management in obese patients Biomed. Pharmacother. 2004, 58, 582-587
15. 2C receptor agonist for the treatment of obesity J. Med. Chem. 2008, 51, 305-313
16. Wong, D.; Sullivan, K.; Heap, G. The pharmaceutical market for obesity therapies Nat. Rev. Drug Discovery 2012, 11, 669-670
17. Colman, E.; Golden, J.; Roberts, M.; Egan, A.; Weaver, J.; Rosebraugh, C. The FDA's assessment of two drugs for chronic weight management N. Engl. J. Med. 2012, 367, 1577-1579
18. Tai, C. L.; Hung, M. S.; Pawar, V. D.; Tseng, S. L.; Song, J. S.; Hsieh, W. P.; Chiu, H. H.; Wu, H. C.; Hsieh, M. T.; Kuo, C. W.; Hsieh, C. C.; Tsao, J. P.; Chao, Y. S.; Shia, K. S. Design, synthesis, and biological evaluation of novel alkenylthiophenes as potent and selective CB1 cannabinoid receptor antagonists Org. Biomol. Chem. 2008, 6, 447-450
19. Chu, C. M.; Hung, M. S.; Hsieh, M. T.; Kuo, C. W.; Suja, T. D.; Song, J. S.; Chiu, H. H.; Chao, Y. S.; Shia, K. S. Bioisosteric replacement of the pyrazole 3-carboxamide moiety of rimonabant. A novel series of oxadiazoles as CB1 cannabinoid receptor antagonists Org. Biomol. Chem. 2008, 6, 3399-3407
20. Tseng, S. L.; Hung, M. S.; Chang, C. P.; Song, J. S.; Tai, C. L.; Chiu, H. H.; Hsieh, W. P.; Lin, Y.; Chung, W. L.; Kuo, C. W.; Wu, C. H.; Chu, C. M.; Tung, Y. S.; Chao, Y. S.; Shia, K. S. Bioisosteric replacement of the pyrazole 5-aryl moiety of N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 4-methyl-1 H -pyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective cannabinoid-1 receptor antagonists J. Med. Chem. 2008, 51, 5397-5412
21. Wu, C. H.; Hung, M. S.; Song, J. S.; Yeh, T. K.; Chou, M. C.; Chu, C. M.; Jan, J. J.; Hsieh, M. T.; Tseng, S. L.; Chang, C. P.; Hsieh, W. P.; Lin, Y.; Yeh, Y. N.; Chung, W. L.; Kuo, C. W.; Lin, C. Y.; Shy, H. S.; Chao, Y. S.; Shia, K. S. Discovery of 2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1 H -pyrazol-3-yl]-1,5,5-trimethyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an active metabolite. A novel, potent and selective cannabinoid-1 receptor inverse agonist with high antiobesity efficacy in DIO mice J. Med. Chem. 2009, 52, 4496-4510
22. Hung, M. S.; Chang, C. P.; Li, T. C.; Yeh, T. K.; Song, J. S.; Lin, Y.; Wu, C. H.; Kuo, P. C.; Amancha, P. K.; Wong, Y. C.; Hsiao, W. C.; Chao, Y. S.; Shia, K. S. Discovery of 1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(2-(4- (trifluoromethyl)phenyl)ethynyl)thiophen-2-yl)- N -(piperidin-1-yl)-1 H -pyrazole-3-carboxamide as a potential peripheral cannabinoid-1 receptor inverse agonist ChemMedChem 2010, 5, 1439-1443
23. Lin, Y.; Shia, K. S.; Hsiao, W. C.; Hsieh, W. P.; Yeh, T. K.; Tseng, S. L.; Hsu, C. Y.; Chao, Y. S.; Hung, M. S. Biphasic suppression of appetite by cannabinoid CB1 receptor antagonists with distinct functional activities Pharmacol. Res. 2010, 62, 337-343
24. Shia, K. S.; Chao, Y. S. Opportunities and potential challenges for the treatment of metabolic syndrome Curr. Top. Med. Chem. 2011, 11, 1420
25. Wu, Y. K.; Yeh, C. F.; Ly, T. W.; Hung, M. S. A new perspective of cannabinoid 1 receptor antagonists: approaches toward peripheral CB1 blockers without crossing the blood-brain barrier Curr. Top. Med. Chem. 2011, 11, 1421-1429
26. Vijayakumar, R. S.; Lin, Y.; Shia, K. S.; Yeh, Y. N.; Hsieh, W. P.; Hsiao, W. C.; Chang, C. P.; Chao, Y. S.; Hung, M. S. Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis, and reduces cardiometabolic risk factors Int. J. Obesity 2012, 36, 999-1006
27. Wittgen, H. G. M.; Greupink, R.; van den Heuvel, J. J. M. W.; van den Broek, P. H. H.; Dinter-Heidorn, H.; Koenderink, J. B.; Russel, F. G. M. Exploiting transport activity of P-glycoprotein at the blood-brain barrier for the development of peripheral cannabinoid type 1 receptor antagonists Mol. Pharm. 2012, 9, 1351-1360
28. Kelder, J.; Grootenhuis, P. D.; Bayada, D. M.; Delbressine, L. P.; Ploemen, J. P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs Pharm. Res. 1999, 16, 1514-1519
29. ven de Waterbeemd, H.; Camenisch, G.; Folkers, G.; Chretien, J. R.; Raevsky, O. A. Estimation of blood-brain barrier crossing of drugs using molecular size and sharp, and H-bonding descriptors J. Drug Targeting 1998, 6, 151-165
30. Lange, J. H.; van der Neut, M. A.; Borst, A. J.; Yildirim, M.; van Stuivenberg, H. H.; van Vliet, B. J.; Kruse, C. G. Probing the cannabinoid CB1/CB2 receptor subtype selectivity limits of 1,2-diarylimidazole-4- carboxamides by fine-tuning their 5-substitution pattern Bioorg. Med. Chem. Lett. 2010, 20, 2770-2775
31. Lee, H. K.; Choi, E. B.; Pak, C. S. The current status and future perspectives of studies of cannabinoid receptor 1 antagonists as anti-obesity agents Curr. Top. Med. Chem. 2009, 9, 482-503
32. Clark, D. E.; Pickett, S. D. Computational methods for the prediction of "drug"-likeness Drug Discovery Today 2000, 5, 49-58
33. Receveur, J. M.; Murray, A.; Linget, J. M.; Nørregaard, P. K.; Cooper, M.; Bjurling, E.; Nielsen, P. A.; Högberg, T. Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood-brain-barrier Bioorg. Med. Chem. Lett. 2010, 20, 453-457
34. Hortala, L.; Rinaldi-Carmona, M.; Congy, C.; Boulu, L.; Sadoun, F.; Fabre, G. Finance, O.; Barth, F. Rational design of a novel peripherally- restricted, orally active CB1 cannabinoid antagonist containing a 2,3-diarylpyrrole motif Bioorg. Med. Chem. Lett. 2010, 20, 4573-4577
35. Sasmal, P. K.; Reddy, D. S.; Talwar, R.; Venkatesham, B.; Balasubrahmanyam, D.; Kannan, M.; Srinivas, P.; Kumar, K. S.; Devi, B. N.; Jadhav, V. P.; Khan, S. K.; Mohan, P.; Chaudhury, H.; Bhuniya, D.; Iqbal, J.; Chakrabarti, R. Novel pyrazole-3-carboxamide derivatives as cannabinoid-1 (CB1) antagonists: Journey from non-polar to polar amides Bioorg. Med. Chem. Lett. 2011, 21, 562-568
36. Sasmal, P. K.; Talwar, R.; Swetha, J.; Balasubrahmanyam, D.; Venkatesham, B.; Rawoof, K. A.; Devi, B. N.; Jadhav, V. P.; Khan, S. K.; Mohan, P.; Reddy, D. S.; Nyavanandi, V. K.; Nanduri, S.; Kumar, K. S.; Kannan, M.; Srinivas, P.; Nadipalli, P.; Chaudhury, H.; Sebastian, V. J. Structure-activity relationship studies of novel pyrazole and imidazole carboxamides as cannabinoid-1 (CB1) antagonists Bioorg. Med. Chem. Lett. 2011, 21, 4913-4918
37. Fulp, A.; Bortoff, K.; Zhang, Y.; Seltzman, H.; Snyder, R.; Maitra, R. Towards rational design of cannabinoid receptor 1 (CB1) antagonists for peripheral selectivity Bioorg. Med. Chem. Lett. 2011, 21, 5711-5714
38. Fulp, A.; Bortoff, K.; Seltzman, H.; Zhang, Y.; Mathews, J.; Snyder, R.; Fennell, T.; Maitra, R. Design and synthesis of cannabinoid receptor 1 antagonists for peripheral selectivity J. Med. Chem. 2012, 55, 2820-2834
39. Fulp, A.; Bortoff, K.; Zhang, Y.; Seltzman, H.; Mathews, J.; Snyder, R.; Fennell, T.; Maitra, R. Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists J. Med. Chem. 2012, 55, 10022-10032
40. Dow, R. L.; Carpino, P. A.; Gautreau, D.; Hadcock, J. R.; Iredale, P. A.; Kelly-Sullivan, D.; Lizano, J. S.; O'Connor, R. E.; Schneider, S. R.; Scott, D. O.; Ward, K. M. Design of a potent CB1 receptor antagonist series: A potential scaffold for peripherally-targeted agents ACS Med. Chem. Lett. 2012, 3, 397-401
41. Chorvat, R. J.; Berbaum, J.; Seriacki, K.; McElroy, J. F. JD-5006 and JD-5037: Peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities Bioorg. Med. Chem. Lett. 2012, 22, 6173-6180
42. Tam, J.; Cinar, R.; Liu, J.; Godlewski, G.; Wesley, D.; Jourdan, T.; Szanda, G.; Mukhopadhyay, B.; Chedester, L.; Liow, J. S.; Innis, R. B.; Cheng, K.; Rice, K. C.; Deschamps, J. R.; Chorvat, R. J.; McElroy, J. F.; Kunos, G. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance Cell Metab. 2012, 16, 167-179
43. Lange, J. H. M.; Kruse, C. G. Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists Drug Discovery Today 2005, 10, 693-702
44. Schwabe, R. F. Endocannabinoids promote hepatic lipogenesis and steatosis through CB1 receptors Hepatology 2005, 42, 959-961
45. Osei-Hyiaman, D.; DePetrillo, M.; Pacher, P.; Liu, J.; Radaeva, S.; Bátkai, S.; Harvey-White, J.; Mackie, K.; Offertáler, L.; Wang, L.; Kunos, G. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity J. Clin. Invest. 2005, 115, 1298-1305
46. Osei-Hyiaman, D.; Liu, J.; Zhou, L.; Godlewski, G.; Harvey-White, J.; Jeong, W.; Bátkai, S.; Marsicano, G.; Lutz, B.; Buettner, C.; Kunos, G. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice J. Clin. Invest. 2008, 118, 3160-3169
47. Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.; Mackie, K.; Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R. L. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors Mol. Pharmacol. 1995, 48, 443-450
48. Frang, H.; Mukkala, V. M.; Syystö, R.; Ollikka, P.; Hurskainen, P.; Scheinin, M.; Hemmilä, I. Nonradioactive GTP binding assay to monitor activation of G protein-coupled receptors Assay Drug Dev. Technol. 2003, 1, 275-280
49. Muccioli, G. G.; Wouters, J.; Charlier, C.; Scriba, G. K. E.; Pizza, T.; Di Pace, P.; De Martino, P.; Poppitz, W.; Poupaert, J. H.; Lambert, D. M. Synthesis and activity of 1,3,5-triphenylimidazolidine-2,4-diones and 1,3,5-triphenyl-2-thioxoimidazolidin-4-ones: Characterization of new CB1 cannabinoid receptor inverse agonists/antagonists J. Med. Chem. 2006, 49, 872-882
50. Trillou, R. C.; Arnone, M.; Delgorge, C.; Gonalons, N.; Keane, P.; Maffrand, J. P.; Soubrie, P. Anti-obesity effect of SR141716A, a CB1 receptor antagonist, in diet-induced obese mice Am. J. Physiol.: Regul., Integr. Comp. Physiol. 2003, 284, 345-353