Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective with no activity against 11β-HSD2 and 17β-HSD1. Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.
Highlights
Series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11b-HSD1
Most of the target compounds with a sulfur linker can be prepared by a coupling reaction of 1-adamantyl bromomethyl ketone with the corresponding commercially available mercaptan in the presence of triethylamine in acetonitrile
Further oxidation of these compounds with meta-chloroperoxybenzoic acid at À10 8C to 0 8C generally produced both the sulfoxide (14, 15, 30–33) and sulfone (16, 17, 34–37) derivatives (Scheme 2), which could be separated by flash column chromatography
Summary
Series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11b-HSD1. 11b-hydroxysteroid dehydrogenase isozymes (11b-HSDs) are microsomal enzymes from the short-chain dehydrogenase/reductase family that catalyse the intracellular conversion of physiologically active glucocorticoids and their inert 11-keto counterparts in specific tissues.[1,2] The 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), highly expressed in liver, adipose tissue and the central nervous system, acts as an NADPHdependent reductase converting cortisone (1) in humans to the active glucocorticoid cortisol (2) (Scheme 1). The 11b-HSD2 isoform catalyses the transformation of cortisol to inactive cortisone and reduces the local concentration of cortisol in specific tissues This mechanism prevents cortisol occupation of mineralocorticoid receptors in the kidney, which may result in sodium retention, hypokalaemia and hypertension.[4,5,6].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
