Discovery of 1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(2-(4-(trifluoromethyl) phenyl)ethynyl)thiophen-2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide as a potential peripheral cannabinoid-1 receptor inverse agonist

ChemMedChem

Volumn 5, Issue 9, 2010, Pages 1439-1443

  Hung, Ming Shiu ^a   Chang, Chun Ping ^a   Li, Ting Chieh ^a   Yeh, Teng Kuang ^a   Song, Jen Shin ^a   Lin, Yinchiu ^a   Wu, Chien Huang ^a   Kuo, Po Chu ^a   Amancha, Prashanth K ^a   Wong, Ying Chieh ^a   Hsiao, Wen Chi ^a   Chao, Yu Sheng ^a   Shia, Kak Shan ^a  

^a NATIONAL HEALTH RESEARCH INSTITUTES   (Taiwan)

Author keywords

Blood brain barrier; Brain to plasma ratio; Cannabinoid 1 receptor; Central nervous system; Diet induced obesity

Indexed keywords

1 (2,4 DICHLOROPHENYL) 4 ETHYL 5 [5 [2 [4 (TRIFLUOROMETHYL)PHENYL]ETHYNYL]THIOPHEN 2 YL] N (PIPERIDIN 1 YL) 1H PYRAZOLE 3 CARBOXAMIDE; CANNABINOID 1 RECEPTOR AGONIST; PYRAZOLE DERIVATIVE; RIMONABANT; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DRUG BINDING; DRUG POTENCY; IC 50; MALE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; RAT; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION;

ANIMALS; ANTI-OBESITY AGENTS; BLOOD-BRAIN BARRIER; DISEASE MODELS, ANIMAL; DRUG EVALUATION, PRECLINICAL; DRUG INVERSE AGONISM; HUMANS; HYPOTHERMIA; MALE; PYRAZOLES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, CANNABINOID, CB1; RECEPTOR, CANNABINOID, CB2; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

EID: 77956411564     PISSN: 18607179     EISSN: 18607187     Source Type: Journal    
DOI: 10.1002/cmdc.201000246     Document Type: Article

References (25)

1. R. I. Wilson, R. A. Nicoll, Science 2002, 296, 678-782.
2. A. C. Howlett, F. Barth, T. I. Bonner, G. Cabral, P. Casellas, W. A. Devane, C. C. Felder, M. Herkenham, K. Mackie, B. R. Martin, R. Mechoulam, R. G. Pertwee, Pharmacol. Rev. 2002, 54, 161-202.
3. a) E. J. Carrier, C. S. Kearn, A. J. Barkmeier, N. M. Breese, W. Yang, K. Nithipatikom, S. L. Pfister, W. B. Campbell, C. J. Hillard, Mol. Pharmacol. 2004, 65, 999-1007;
4. b) S. Munro, K. L. Thomas, M. Abu-Shaar, Nature 1993, 365, 61-65.
5. a) P. Goya, N. Jagerovic, Expert Opin. Ther. Pat. 2000, 10, 1529-1538;
6. b) P. Cowley, J. Adam, Expert Opin. Ther. Pat. 2002, 12, 1475-1489;
7. c) D. R. Janero, A. Makriyannis, Expert Opin. Emerging Drugs 2009, 14, 43-65.
8. a) H. Bays, C. Dujovne, Am. J. Cardiovasc. Drugs 2002, 2, 245-253;
9. b) A. Kaya, N. Aydin, P. Topsever, Filiz, Oztürk, Daǧar, E. Kilinç, C. Ekmekcioglu, Biomed. Pharmacother. 2004, 58, 582-587;
10. c) D. W. Clark, M. Harrison-Woolrych, BMJ 2004, 329, 1316.
11. J. LoVerme, Duranti, Tontini, G. Spadoni, Mor, S. Rivara, N. Stella, C. Xu, G. Tarzia, D. Piomelli, Bioorg. Med. Chem. Lett. 2009, 19, 639-643.
12. a) J. F. Mcelroy, R. J. Chorvat, (Jenrin Discovery, West Chester, USA), WO/2007/131219, 2007;
13. b) J. F. Mcelroy, R. J. Chorvat, (Jenrin Discovery, Wilmington, USA), WO/2009/033125, 2009;
14. c) Peripheral-acting CB1 antagonists discovered by Jenrin Discovery are reported to play a significant role in the treatment of metabolic disorders with reducing risks of psychiatric adverse effects; Non-brain penetrant CB1 antagonists from Jerin Discovery show beneficial effects in treating diabetes and obesity (oral presentation), 26th Annual Scientific Meeting of the Obesity Society, October 3-7, 2008 (Phoenix, USA);
15. d) JD-5006, a compound with low brain exposure compared to previously developed CB1 blockers (e.g., 1), may represent a safer alternative for the treatment of liver disease, diabetes and related metabolic disorders, and as exemplified, significant weight loss may not be required for CB1-mediated antidiabetic efficacy. The structure of JD-5006 has not yet been released; Peripheral selective CB1-antagonists as metabolic disorder therapeutics devoid of psychiatric liabilities (oral presentation), 7th International Symposium for Chinese Medicinal Chemists, February 1-5, 2010 (Taiwan).
16. a) J. M. Receveur, A. Murray, J. M. Linget, P. K. Nørregaard, M. Cooper, E. Bjurling, P. A. Nielsen, T. Högberg, Bioorg. Med. Chem. Lett. 2010, 20, 453-457;
17. b) 7TM Pharma (http://www.7tm.com/); 7TM Pharma announced the selection of a new preclinical development candidate, TM38837, for the treatment of obesity and type II diabetes (http://www.7tm.com/R-D/Metabolic-Disorders/ TM38837.aspx; Last accessed: July 8, 2010); however, the structure of TM38837 has not been released yet.
18. H. K. Lee, E. B. Choi, C. S. Pak, Curr. Top. Med. Chem. 2009, 9, 482-503 and references therein.
19. M. H. Son, H. D. Kim, Y. N. Chae, M. K. Kim, C. Y. Shin, G. J. Ahn, S. H. Choi, E. K. Yang, K. J. Park, H. W. Chae, H. S. Moon, S. H. Kim, Y. G. Shin, S. H. Yoon, Int. J. Obes. 2010, 34, 547-556.
20. T. M. Fong, S. B. Heymsfield, Int. J. Obes. 2009, 33, 947-955.
21. S. L. Tseng, M. S. Hung, C. P. Chang, J.-S. Song, C. L. Tai, H. H. Chiu, W. P. Hsieh, Y. Lin, W. L. Chung, C. W. Kuo, C. H. Wu, C. M. Chu, Y. S. Tung, Y. S. Chao, K. S. Shia, J. Med. Chem. 2008, 51, 5397-5412.
22. K. Kobayashi, A. Sugie, M. Takahashi, K. Masui, A. Mori, Org. Lett. 2005, 7, 5083-5085 and references therein.
23. S. A. Hitchcock, L. D. Pennington, J. Med. Chem. 2006, 49, 7559-7583 and references therein.
24. J. H. M. Lange, C. G. Kruse, Drug Discovery Today 2005, 10, 693-702 and references therein.
25. S. M. Rawls, J. Cabassa, M. W. Adler, E. B. Geller, J. Pharmacol. Exp. Ther. 2002, 301, 963-968.