Identification of novel mPGES-1 inhibitors through screening of a chemical library

[摘要] Human microsomal prostaglandin E synthase-1 (mPGES-1) is an emerging drug target for inflammatory disorders and cancer suppression. Therefore, it is crucially important to discover mPGES-1 inhibitors with novel structural scaffolds for the development of anti-inflammatory drugs. Here, we report the mPGES-1 inhibitors identified through screening of a chemical library. Initial screening of 1841 compounds out of 200,000 in a master library resulted in 9 primary hits. From the master library, 387 compounds that share the scaffold structure with the 9 primary hit compounds were selected, of which 3 compounds showed strong inhibitory activity against mPGES-1 having IC50 values of 1-3 mu M. Notably, a derivative of sulfonylhydrazide, compound 3b, inhibited the LPS-induced PGE(2) production in RAW 264.7 cells. This compound showed novel scaffold structure compared to the known inhibitors of mPGES-1, suggesting that it could be further developed as a potent mPGES-1 inhibitor. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.

[发布日期] 2012-12-15

[关键词] mPGES-1;Screening;Inhibitors;Anti-inflammatory drug;Modeling