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Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) have considerable potential as treatments for metabolic diseases, such as diabetes mellitus type 2 or obesity. Here, we report the discovery and synthesis of a series of novel benzothiazole derivatives and their inhibitory activities against 11beta-HSD1 from human hepatic microsomes measured using a radioimmunoassay (RIA) method. The benzothiazole derivatives 1 and 2 showed greater than 80% inhibition for 11beta-HSD1 at 10 microM and exhibited IC50 values in the low micromolar range. The preliminary SAR study suggested the introduction of a chlorine substituent at the 4 position of the benzothiazole ring greatly enhanced the inhibitory activities. Docking studies with the benzothiazole derivative 1 into the crystal structure of human 11beta-HSD1 revealed how the molecule may interact with the enzyme and cofactor.

Original publication

DOI

10.1016/j.mce.2005.10.022

Type

Journal article

Journal

Mol Cell Endocrinol

Publication Date

27/03/2006

Volume

248

Pages

214 - 217

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Benzothiazoles, Enzyme Inhibitors, Humans, Inhibitory Concentration 50, Microsomes, Liver, Protein Conformation, Structure-Activity Relationship, Thiazoles