1. Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity
- Author
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Soongyu Choi, Zhonghua Zhang, Gan Wang, Anish Konkar, Su-Ellen Brown, Susan Tomlinson, Roger A. Smith, Ning Su, Theresa Tritto, Astrid A. Ortiz, Stephan-Nicholas Wirtz, Ronald Mays, Jennifer Natoli, Christiana Akuche, Stephen J. O’Connor, Wong Wai C, Christy Taing, Rico Lavoie, Zahra Fathi, Shihong Ying, Jianmei Fan, Susan Jenkins, Harold C. E. Kluender, Furahi Achebe, and Xiao-Fan Yang
- Subjects
Stereochemistry ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Receptor, Cannabinoid, CB1 ,Oral administration ,Amide ,Drug Discovery ,medicine ,Animals ,Imidazole ,Moiety ,Obesity ,Receptors, Cannabinoid ,Molecular Biology ,Dose-Response Relationship, Drug ,Body Weight ,Organic Chemistry ,Imidazoles ,Antagonist ,Rats ,Rats, Zucker ,chemistry ,Anorectic ,Molecular Medicine ,Anti-Obesity Agents ,Cannabinoid - 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 Ki = 3.7 nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.
- Published
- 2007
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