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

…, R Lavoie, R Mays, J Natoli, SJ O'Connor…

Index: Smith, Roger A.; Fathi, Zahra; Achebe, Furahi; Akuche, Christiana; Brown, Su-Ellen; Choi, Soongyu; Fan, Jianmei; Jenkins, Susan; Kluender, Harold C.E.; Konkar, Anish; Lavoie, Rico; Mays, Ronald; Natoli, Jennifer; O'Connor, Stephen J.; Ortiz, Astrid A.; Su, Ning; Taing, Christy; Tomlinson, Susan; Tritto, Theresa; Wang, Gan; Wirtz, Stephan-Nicholas; Wong, Wai; Yang, Xiao-Fan; Ying, Shihong; Zhang, Zhonghua Bioorganic and Medicinal Chemistry Letters, 2007 , vol. 17, # 10 p. 2706 - 2711

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Citation Number: 12

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 ...