Benzothiazole derivatives as novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.

Abstract

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.

• Authors: Xiangdong Su, Nigel Vicker, Dharshini Ganeshapillai, Andrew Smith, Atul Purohit, Michael J Reed, Barry V L Potter
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 248 Issue 1-2 Pg. 214-7 (Mar 27 2006) ISSN: 0303-7207 [Print] Ireland
• PMID: 16325333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzothiazoles
• Enzyme Inhibitors
• Thiazoles
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• benzothiazole

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors, chemistry)
• Benzothiazoles
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Inhibitory Concentration 50
• Microsomes, Liver (enzymology)
• Protein Conformation
• Structure-Activity Relationship
• Thiazoles (chemistry, pharmacology)