Abstract
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 IC50 values in the 100nM range. These compounds are also highly selective 11β-HSD1 inhibitors with no activity against 11β-HSD2 and 17β-HSD1. Compound 15 (IC50=114nM) 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 (IC50=280nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification.
Highlights
The modulation of 11b-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity
We report the synthesis and the structure–activity relationships of some adamantyl carboxamide and adamantyl acetamide compounds as potent inhibitors of 11b-HSD1
Target compounds with an adamantyl group were synthesized from 1-adamantyl carbonyl chloride or 1-adamantyl acetic acid through an amide coupling reaction with various amines under standard conditions as illustrated in Scheme 2
Summary
11b-Hydroxysteroid dehydrogenase isozymes catalyze the intracellular conversion of inert 11-keto glucocorticoids to physiologically active glucocorticoids in specific tissues, and vice versa. 11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) functions as an NADPH-dependent reductase converting cortisone [1] in humans to the active glucocorticoid cortisol [2] (Scheme 1). 11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) functions as an NADPH-dependent reductase converting cortisone [1] in humans to the active glucocorticoid cortisol [2] (Scheme 1). This endoplasmic reticulum-associated enzyme is highly expressed in liver, adipose tissue and in the central nervous system. The relationship of 11b-HSD1 mediated glucocorticoid regulation with metabolic disorders, such as obesity and type 2 diabetes has been well established by studies using genetically- modified rodent models. Preclinical studies show that modulation of 11b-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity.. The mid-stage study of INCB013739 demonstrated that treatment of type 2 diabetes mellitus patients with INCB013739 for 28 days significantly improved hepatic and peripheral insulin sensitivity and reduced fasting
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