| 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. | |
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MedLine Citation:
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PMID: 19530697 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 52 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-16 Completed Date: 2009-08-25 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 4496-510 Citation Subset: IM |
Affiliation:
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Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan, ROC. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Obesity Agents / chemistry, metabolism, pharmacology, therapeutic use Cell Line Diabetes Mellitus / chemically induced, drug therapy*, metabolism Diet Drug Discovery* Drug Inverse Agonism* Eating / drug effects Humans Imidazoles / chemistry, metabolism*, pharmacology*, therapeutic use Inhibitory Concentration 50 Male Mice Mice, Obese Rats Receptor, Cannabinoid, CB1 / agonists* Receptor, Cannabinoid, CB2 / agonists Substrate Specificity Thiones / chemistry, metabolism*, pharmacology*, therapeutic use |
| Chemical | |
Reg. No./Substance:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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