Identification of new γ-hydroxybutenolides that preferentially inhibit the activity of mPGES-1

Microsomal prostaglandin E2 synthase-1 (mPGES-1) has been recognized as novel, promising drug target for anti-inflammatory and anticancer drugs. mPGES-1 catalyzes the synthesis of the inducible prostaglandin E2 in response to pro-inflammatory stimuli, rendering this enzyme extremely interesting in drug discovery process owing to the drastic reduction of the severe side effects typical for traditional non-steroidal anti-inflammatory drugs. In the course of our investigations focused on this topic, we identified two interesting molecules bearing the γ-hydroxybutenolide scaffold which potently inhibit the activity of mPGES-1. Notably, the lead compound 2c that inhibited mPGES-1 with IC50 = 0.9 μM, did not affect other related enzymes within the arachidonic acid cascade.

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is the terminal enzyme involved in the synthesis of the inducible prostaglandin E2 in response to pro-inflammatory stimuli. It represents an extremely interesting target-enzyme for the development of safer anti-inflammatory drugs devoid of severe side effects typical for traditional drugs. In the course of our investigations focused on this topic, we identified two very interesting γ-hydroxybutenolide derivatives able to efficiently inhibit the catalytic activity of mPGES-1. Specifically, we discovered compound 2d that inhibited mPGES-1 with IC50 = 5.6 μM and, above all, compound 2c that inhibited the target-enzyme with IC50 = 0.9 μM without affecting other related enzymes within the arachidonic acid cascade.Figure optionsDownload as PowerPoint slide