Optimization of novel di-substituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors

…, S Caille, M DeGraffenreid, X He, R Hungate…

Index: McMinn, Dustin L.; Rew, Yosup; Sudom, Athena; Caille, Seb; DeGraffenreid, Michael; He, Xiao; Hungate, Randall; Jiang, Ben; Jaen, Juan; Julian, Lisa D.; Kaizerman, Jacob; Novak, Perry; Sun, Daqing; Tu, Hua; Ursu, Stefania; Walker, Nigel P.C.; Yan, Xuelei; Ye, Qiuping; Wang, Zhulun; Powers, Jay P. Bioorganic and Medicinal Chemistry Letters, 2009 , vol. 19, # 5 p. 1446 - 1450

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Citation Number: 18

Abstract

Novel 4, 4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11β-HSD1 in a rat pharmacodynamic model (ED50= 10mg/kg).