title: 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.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Bath BA2 7AY, UK.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Su
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Dharshini
authors.initials: D
authors.lastname: Ganeshapillai
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052160:Benzothiazoles; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000201:enzymology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C005465:benzothiazole