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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Obesity Agents / chemistry
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Anti-Obesity Agents / metabolism
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Anti-Obesity Agents / pharmacology
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Anti-Obesity Agents / therapeutic use
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Cell Line
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Diabetes Mellitus / chemically induced
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Diabetes Mellitus / drug therapy*
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Diabetes Mellitus / metabolism
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Diet
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Drug Discovery*
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Drug Inverse Agonism*
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Eating / drug effects
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Humans
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Imidazoles / chemistry
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Imidazoles / metabolism*
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Imidazoles / pharmacology*
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Imidazoles / therapeutic use
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Inhibitory Concentration 50
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Male
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Mice
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Mice, Obese
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Rats
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Receptor, Cannabinoid, CB1 / agonists*
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Receptor, Cannabinoid, CB2 / agonists
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Substrate Specificity
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Thiones / chemistry
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Thiones / metabolism*
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Thiones / pharmacology*
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Thiones / therapeutic use
Substances
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2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazol-3-yl)-1,5,5-trimethyl-1,5-dihydroimidazol-4-thione
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Anti-Obesity Agents
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Imidazoles
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2
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Thiones
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imidazole