Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA

Abstract The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2 , which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2 , the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro , 11 suppressed PGE 2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors.