Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11beta-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

doi:10.1016/j.bmcl.2009.01.058

Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11beta-HSD1 inhibitors

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1797-801. doi: 10.1016/j.bmcl.2009.01.058. Epub 2009 Jan 23.

Authors

Yosup Rew¹, 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

Affiliation

¹ Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

PMID: 19217779
DOI: 10.1016/j.bmcl.2009.01.058

Abstract

Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series 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.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry
Benzamides / chemical synthesis*
Benzamides / pharmacology
Crystallography, X-Ray / methods
Diabetes Mellitus, Type 2 / drug therapy*
Drug Design
Hepatocytes / drug effects
Humans
Inhibitory Concentration 50
Insulin / metabolism*
Microsomes / metabolism
Models, Chemical
Molecular Structure
Piperidines / chemistry*
Solubility
Structure-Activity Relationship

Substances

Benzamides
Insulin
Piperidines
benzamide
11-beta-Hydroxysteroid Dehydrogenase Type 1