title: Small molecule 11β-hydroxysteroid dehydrogenase type 1 inhibitors.
abstract: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the interconversion of inactive cortisone to active cortisol in a NADPH dependent manner. Excess cortisol or 11β-HSD1 leads to insulin resistance and metabolic syndrome. Inhibition of 11β-HSD1 activity has been pursued vigorously by the pharmaceutical industry as a potential therapeutic strategy for the treatment of type 2 diabetes. As a result, a large number of chemical classes have been identified as potent and selective small molecule inhibitors for 11β-HSD1. Here we review the recent progress in the discovery and development of small molecule inhibitors of 11β-HSD1 by highlighting the medicinal chemistry, SAR, in vivo pharmacodynamic effects and efficacy of a few representative classes of inhibitors in models of diabetes. Furthermore, we also review the structural characteristics of each class of inhibitors by analyzing the inhibitor co-crystal structures of 11β-HSD1.
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. daqings@amgen.com
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1