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Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2007 May 15; Vol. 17 (10), pp. 2706-11. Date of Electronic Publication: 2007 Mar 12. - Publication Year :
- 2007
-
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.
- Subjects :
- 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 Relationship
Anti-Obesity Agents pharmacology
Body Weight drug effects
Receptor, Cannabinoid, CB1 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0960-894X
- Volume :
- 17
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 17383180
- Full Text :
- https://doi.org/10.1016/j.bmcl.2007.03.011