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Discovery of adamantyl heterocyclic ketones as potent 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors


Reference:

Su, X., Vicker, N., Thomas, M. P., Pradaux-Caggiano, F., Halem, H., Culler, M. D. and Potter, B. V. L., 2011. Discovery of adamantyl heterocyclic ketones as potent 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors. ChemMedChem, 6 (8), pp. 1439-1451.

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Official URL:

http://dx.doi.org/10.1002/cmdc.201100144

Abstract

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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 11 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11 beta-HSD1 and are selective with no activity against 11 beta-HSD2 and 17 beta-HSD1. Selected potent 11 beta-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.

Details

Item Type Articles
CreatorsSu, X., Vicker, N., Thomas, M. P., Pradaux-Caggiano, F., Halem, H., Culler, M. D. and Potter, B. V. L.
DOI10.1002/cmdc.201100144
DepartmentsFaculty of Science > Pharmacy & Pharmacology
Faculty of Science > Chemistry
RefereedYes
StatusPublished
ID Code25812

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