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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 6; pp. 1797 - 1801
• Main Authors: Rew, Yosup, McMinn, Dustin L., Wang, Zhulun, He, Xiao, Hungate, Randall W., Jaen, Juan C., Sudom, Athena, Sun, Daqing, Tu, Hua, Ursu, Stefania, Villemure, Elisia, Walker, Nigel P.C., Yan, Xuelei, Ye, Qiuping, Powers, Jay P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.03.2009; Elsevier
• Subjects: 11β-HSD1; Biological and medical sciences; Cyclohexyl benzamide; General and cellular metabolism. Vitamins; Hepatocyte stability; Insulin sensitivity; Medical sciences; Microsomal stability; Pharmacology. Drug treatments; Piperidyl benzamide; PXR; Type II diabetes; Hepatocyte stability; Insulin sensitivity; Microsomal stability; Type II diabetes; Cyclohexyl benzamide; PXR; 11β-HSD1; Piperidyl benzamide; Type 2 diabetes; Pancreatic hormone; Cyclopropane derivatives; Rat; Isozyme; Microsome; Optimization; Protein hormone; Hepatocyte; Structure activity relation; Tertiary alcohol; 11β-Hydroxysteroid dehydrogenase; Piperidine derivatives; Chemical synthesis; Stability; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Bioavailability; In vitro; Insulin; In vivo; Vertebrata; Sensitivity; Metabolic stability; Mammalia; Animal; Benzamide derivatives; Oxidoreductases; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.058

The discovery and optimization of a piperidyl benzamide series of 11β-HSD1 inhibitors is reported. Discovery and optimization of a piperidyl benzamide series of 11β-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.