Adamantyl carboxamides and acetamides as potent human 11?-hydroxysteroid dehydrogenase type 1 inhibitors.

ABSTRACT: The modulation of 11?-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11?-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11?-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC(50) values in the 100 nM range. These compounds are also highly selective 11?-HSD1 inhibitors with no activity against 11?-HSD2 and 17?-HSD1. Compound 15 (IC(50)=114 nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC(50)=280 nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification.

SUBMITTER: Su X 

PROVIDER: S-EPMC3510433 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature