ABSTRACT
Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.
Subject(s)
Anti-Obesity Agents/pharmacology , Body Weight/drug effects , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , Anti-Obesity Agents/therapeutic use , Dose-Response Relationship, Drug , Imidazoles/pharmacology , Imidazoles/therapeutic use , Obesity/drug therapy , Rats , Rats, Zucker , Receptors, Cannabinoid/metabolism , Structure-Activity RelationshipABSTRACT
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , 17-Hydroxysteroid Dehydrogenases/metabolism , Animals , Cell Line , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Macaca fascicularis , Pyrrolidinones/chemical synthesis , Rats , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesisABSTRACT
4,5-Disubstituted cis-pyrrolidinones were investigated as inhibitors of type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Early structure-activity relationship patterns for this class of compounds are discussed.