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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 Jul 23; Vol. 52 (14), pp. 4496-510. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Animals
Anti-Obesity Agents chemistry
Anti-Obesity Agents metabolism
Anti-Obesity Agents pharmacology
Anti-Obesity Agents therapeutic use
Cell Line
Diabetes Mellitus chemically induced
Diabetes Mellitus metabolism
Diet
Eating drug effects
Humans
Imidazoles chemistry
Imidazoles therapeutic use
Inhibitory Concentration 50
Male
Mice
Mice, Obese
Rats
Receptor, Cannabinoid, CB2 agonists
Substrate Specificity
Thiones chemistry
Thiones therapeutic use
Diabetes Mellitus drug therapy
Drug Discovery
Drug Inverse Agonism
Imidazoles metabolism
Imidazoles pharmacology
Receptor, Cannabinoid, CB1 agonists
Thiones metabolism
Thiones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19530697
- Full Text :
- https://doi.org/10.1021/jm900471u