Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study
文摘
Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound class="boldFont">1 (IC50 = 5700 nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent optimization led to the identification of the potent lead compound class="boldFont">8n with IC50 values of 4.5 and 6.9 nM, respectively, against LPS-induced PGE2 production and NO production in RAW 264.7 macrophage cells. In addition, class="boldFont">8n was about 30- and >150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC50 = 70 nM) than MK-886 and hit compound class="boldFont">1, respectively. Molecular docking suggests that compound class="boldFont">8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 enzyme.