Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11b-HSD1 inhibitors Yosup Rew * , Dustin L. McMinn, Zhulun Wang, Xiao He, Randall W. Hungate, Juan C. Jaen   , Athena Sudom, Daqing Sun, Hua Tu, Stefania Ursu, Elisia Villemure, Nigel P. C. Walker, Xuelei Yan, Qiuping Ye, Jay P. Powers   Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA article info Article history: Received 16 December 2008 Revised 15 January 2009 Accepted 16 January 2009 Available online 23 January 2009 Keywords: 11b-HSD1 Type II diabetes Insulin sensitivity Cyclohexyl benzamide Piperidyl benzamide PXR Microsomal stability Hepatocyte stability abstract Discovery and optimization of a piperidyl benzamide series of 11b-HSD1 inhibitors is described. This ser- ies was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives. Ó 2009 Elsevier Ltd. All rights reserved. One of the key regulatory roles of glucocorticoids is glucose homeostasis. In this regard, glucocorticoids regulate gluconeogen- esis in the liver and inhibit peripheral glucose uptake in muscle and adipose tissue. 11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1), an NADPH-dependent reductase, is a key enzyme that converts the inactive glucocorticoid cortisone to the active gluco- corticoid hormone cortisol in liver, adipose, and brain tissues. Excessive concentrations of glucocorticoids in the liver and adipose tissue can lead to glucose intolerance and insulin resistance. There- fore, selective inhibition of the 11b-HSD1 enzyme has been consid- ered as a promising strategy to improve insulin sensitivity and treat type II diabetes. 1,2 Previously we reported on a series of cyclohexyl benzamide derivatives, exemplified by compound 1, as potent 11b-HSD1 inhibitors (Fig. 1). 3 Compound 1 exhibited excellent in vitro inhibi- tion of human 11b-HSD1 enzyme and favorable pharmacokinetic profiles in the rat, cynomolgus monkey, and dog. Furthermore, compound 1 showed a dose-dependent decrease in adipose 11b- HSD1 activity in a monkey ex vivo pharmacodynamic model. 3 However, 1 exhibited low micromolar range in vitro cytotoxicity in HeLa cells (IC 50 = 2.5 lM). 4 The X-ray co-crystal structure of 1 with the 11b-HSD1 enzyme showed that the pyridyl ring points toward the solvent exposed re- gion of the protein dimer interface and does not make any discern- able specific interaction with the active site of the protein. 3 Combined with our initial SAR, 3 this gave some indication that the core cyclohexyl benzamide motif was the essential binding component of these molecules. We hypothesized that, by replacing the pyridyl group with other functional groups, we could modulate physicochemical properties without disrupting critical interactions with the enzyme. Moreover, in addition to enhancing the structural diversity of compounds at the 4-position of the cyclohexane ring, 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.01.058 * Corresponding author. Tel.: +1 650 244 2682. E-mail address: yrew@amgen.com (Y. Rew).   Currently at ChemoCentryx, Inc., Mountain View, CA 94043, USA. CF 3 HO N O hHSD1 SPA IC 50 = 1.4 nM h293 IC 50 = 5.8 nM h293 ( 3% HSA) IC 50 = 124 nM N 1 Figure 1. Representative cyclohexyl benzamide 11b-HSD1 inhibitor. 3,8 Bioorganic & Medicinal Chemistry Letters 19 (2009) 1797–1801 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl