Optimization of novel di-substituted cyclohexylbenzamide derivatives as potent 11b-HSD1 inhibitors q Dustin L. McMinn * , Yosup Rew, Athena Sudom, Seb Caille, Michael DeGraffenreid, Xiao He, Randall Hungate, Ben Jiang, Juan Jaen   , Lisa D. Julian, Jacob Kaizerman, Perry Novak, Daqing Sun, Hua Tu, Stefania Ursu, Nigel P. C. Walker, Xuelei Yan, Qiuping Ye, Zhulun Wang, Jay P. Powers   Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA article info Article history: Received 11 November 2008 Revised 7 January 2009 Accepted 12 January 2009 Available online 15 January 2009 Keywords: 11b-HSD1 Diabetes Metabolic syndrome Hydroxysteroid dehydrogenase Cardiovascular disease Cyclohexylbenzamides abstract Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11b-HSD1 were optimized to account for lia- bilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A repre- sentative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11b-HSD1 in a rat pharmacodynamic model (ED 50 = 10 mg/kg). Ó 2009 Elsevier Ltd. All rights reserved. In humans, 11b-HSD1 catalyzes the reduction of the inactive glucocorticoid cortisone to its active form, cortisol. 2 Glucocorticoid balance is checked by the hypothalamic-pituitary-adrenal (HPA) axis 3 and reversion of cortisol to cortisone by isozyme 11b- HSD2. 4 Upon binding to the glucocorticoid receptor, cortisol positively regulates glucose production. Excessive hepatic glucose production and the functional antagonism of glucocorticoids to- wards insulin action contribute to the diabetic state. Therefore, aug- mented regulation of cortisol levels via inhibition of 11b-HSD1 may be a potential therapy for treatment of diabetes. 5 Inhibitors of 11b- HSD1 may also serve as treatment for ‘metabolic syndrome.’ Unreg- ulated overexpession of cortisol is manifested in Cushing’s disease. Symptoms associated with this disease are typical metabolic syndrome indicators (visceral obesity, reduced insulin sensitivity, dyslipidemia, and high blood pressure) 6 and are reversible upon surgical correction of glucocorticoid over-production. 7 In addition to Cushing’s disease, genetic evidence for the role of 11b-HSD1 in diabetes and obesity has been illustrated in separate experiments involving fat-specific 11b-HSD1 overexpression 8 and liver-specific 11b-HSD1 knock-out mice models. 9 Animals in the former experiment displayed increased levels of gluconeogenesis, visceral obesity, and triglyceride production coupled with impaired insulin sensitivity. In contrast, 11b-HSD1 knock-out mice showed improved glucose tolerance and insulin sensitivity. Moreover, stud- ies utilizing fat-specific overexpression of 11b-HSD2 in mice dem- onstrate that such animals are resistant to diet-induced obesity. Interestingly, studies in monozygotic twins where one of the twins is obese suggest that relative overexpression of 11b-HSD1 in fat tissues of the obese twin may present as an acquired defect of endocrinology as opposed to a genetic dysfunction. 10 Inhibition of 11b-HSD1 may also retard the development of atherosclerosis. 11 Given their potential for treatment of metabolic syndrome, diabe- tes, and cardiovascular disease, inhibitors of 11b-HSD1 are of active interest to the pharmaceutical industry. 12 We have previously disclosed optimization of potency and met- abolic stability for a series of trans-4-substituted cyclohexylbenza- mide-based 11b-HSD1 inhibitors (Table 1). 13 Some members of this series, such as compound 1, showed moderate PXR activation in vitro. 14 This liability proved manageable by increasing polarity within the otherwise hydrophobic trans-4-substituent (com- pounds 2, 4, and 6). 13a Although 2, 4, and 6 elicited minimal PXR activation, it was recently discovered that these compounds exhib- ited appreciable cytotoxicity in vitro. 15 In contrast, cis-isomers of 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.01.026 q See Ref. 1. * Corresponding author. Tel.: +1 650 244 2595. E-mail address: dmcminn@amgen.com (D.L. McMinn).   Present address: ChemoCentryx, Inc., Mountain View, CA 94093, USA. Bioorganic & Medicinal Chemistry Letters 19 (2009) 1446–1450 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl