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The modulation of 11β-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 11β-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11β-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 11β-HSD1 inhibitors with no activity against 11β-HSD2 and 17β-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.

Original publication

DOI

10.1016/j.bmc.2012.08.056

Type

Journal article

Journal

Bioorg Med Chem

Publication Date

01/11/2012

Volume

20

Pages

6394 - 6402

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Acetamides, Adamantane, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Dose-Response Relationship, Drug, Drug Discovery, Enzyme Inhibitors, HEK293 Cells, Humans, Models, Molecular, Molecular Structure, Structure-Activity Relationship