Selective inducible microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from an oxicam template

Here we describe the SAR of a series of potent and selective mPGES-1 inhibitors based on an oxicam template. Compound 13j demonstrated low nanomolar mPGES-1 inhibition in an enzyme assay. In addition, it displayed PGE2 inhibition in a cell-based assay (0.42 μM) and had over 238-fold selectivity for mPGES-1 over COX-2 and over 200-fold selectivity for mPGES-1 over 6-keto PGF1α.

Graphical abstractThe design and synthesis of a series of potent and selective mPGES-1 inhibitors based on an oxicam template are described. Our SAR studies allowed us to optimize this series resulting in the identification of compound 13j which demonstrated potent inhibition in both enzyme and cellular assay. This series of compounds illustrated good mPGES-1 inhibition along with good selectivity over COX-2 and 6-keto PGF1α.Figure optionsDownload full-size imageDownload as PowerPoint slide