Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity.

Article Details

Citation
Copy to clipboard

Smith RA, Fathi Z, Achebe F, Akuche C, Brown SE, Choi S, Fan J, Jenkins S, Kluender HC, Konkar A, Lavoie R, Mays R, Natoli J, O'Connor SJ, Ortiz AA, Su N, Taing C, Tomlinson S, Tritto T, Wang G, Wirtz SN, Wong W, Yang XF, Ying S, Zhang Z

Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity.

Bioorg Med Chem Lett. 2007 May 15;17(10):2706-11. Epub 2007 Mar 12.

PubMed ID
17383180 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
RimonabantCannabinoid receptor 1Ki (nM)1.1N/AN/ADetails