Purpose Microsomal prostaglandin E synthase-1 (mPGES-1), functionally coupled with COX-2, is an inducible prostaglandin E synthase in response to pro-inflammatory stimuli and, therefore, represents a novel target for the development of anti-inflammatory drugs for therapeutic treatment of acute and chronic inflammatory disorders. The aim of this study is to rationally design and synthesize new mPGES-1 inhibitors that could become next generation of inflammatory drugs. Methods Starting from our recently discovered new inhibitors identified from structure-based virtual screening, we carried out de novo design of new compounds as possible inhibitors against mPGES-1. The computational design was followed by organic synthesis and in vitro activity assays for their inhibitory efficacies against mPGES-1 and COX enzymes (COX-1 and COX-2). Results A series of new compounds as potent inhibitors against mPGES-1 have been successfully designed, synthesized, and tested. Most of these compounds were capable of inhibiting mPGES-1 with sub-micromolar potency (IC50 = 20 to 900 nM). Further in vitro assays against other off targets including COX-2 indicated that these new compounds can selectively inhibit mPGES-1. Conclusion The structure-based computational design, followed by synthesis and in vitro assays for evaluating both potency and selectivity, has led to the discovery of a set of novel, potent and selective mPGES-1 inhibitors.

Rational design, synthesis, and in vitro evaluation of mPGES-1 inhibitors as next-generation of anti-inflammatory drugs

253rd National Meeting (2017)

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