Document Detail

Discovery of 2-[5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-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.
MedLine Citation:
PMID:  19530697     Owner:  NLM     Status:  MEDLINE    
By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB1 inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.
Chien-Huang Wu; Ming-Shiu Hung; Jen-Shin Song; Teng-Kuang Yeh; Ming-Chen Chou; Cheng-Ming Chu; Jiing-Jyh Jan; Min-Tsang Hsieh; Shi-Liang Tseng; Chun-Ping Chang; Wan-Ping Hsieh; Yinchiu Lin; Yen-Nan Yeh; Wan-Ling Chung; Chun-Wei Kuo; Chin-Yu Lin; Horng-Shing Shy; Yu-Sheng Chao; Kak-Shan Shia
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  52     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-16     Completed Date:  2009-08-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4496-510     Citation Subset:  IM    
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan, ROC.
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MeSH Terms
Anti-Obesity Agents / chemistry,  metabolism,  pharmacology,  therapeutic use
Cell Line
Diabetes Mellitus / chemically induced,  drug therapy*,  metabolism
Drug Discovery*
Drug Inverse Agonism*
Eating / drug effects
Imidazoles / chemistry,  metabolism*,  pharmacology*,  therapeutic use
Inhibitory Concentration 50
Mice, Obese
Receptor, Cannabinoid, CB1 / agonists*
Receptor, Cannabinoid, CB2 / agonists
Substrate Specificity
Thiones / chemistry,  metabolism*,  pharmacology*,  therapeutic use
Reg. No./Substance:
0/2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazol-3-yl)-1,5,5-trimethyl-1,5-dihydroimidazol-4-thione; 0/Anti-Obesity Agents; 0/Imidazoles; 0/Receptor, Cannabinoid, CB1; 0/Receptor, Cannabinoid, CB2; 0/Thiones; 288-32-4/imidazole

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