Characterization of 3, 3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors. Issue 19 (1st October 2016) - Kuklish, Steven L.
Graphical abstract: Abstract: Here we report on novel, potent 3, 3-dimethyl substituted N -aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7 nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30 μM, and failed to inhibit human mPGES-2 at 62.5 μM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2 . In dog, 14 had oral bioavailability (74%), clearance (3.62 mL/(min*kg)) and volume of distribution ( V d, ss = 1.6 L/kg) values within our target ranges. For these reasons, 14 was selected for further study.