Characterization of 3, 3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: Kuklish, Steven L.; Antonysamy, Stephen; Bhattachar, Shobha N.; Chandrasekhar, Srinivasan; Fisher, Matthew J.; Fretland, Adrian J.; Gooding, Karen; Harvey, Anita; Hughes, Norman E.; Luz, John G.; Manninen, Peter R.; McGee, James E.; Navarro, Antonio; Norman, Bryan H.; Partridge, Katherine M.; Quimby, Steven J.; Schiffler, Matthew A.; Sloan, Ashley V.; Warshawsky, Alan M.; York, Jeremy S.; Yu, Xiao-Peng
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 19(2016)
• Page Start: 4824
• Page End: 4828
• Publication Date: 2016-10-01
• Subjects: mPGES-1 -- Prostaglandin pathway -- Dog bioavailability -- Biomarker; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.023
• Languages: English
• ISSNs: 0960-894X

Abstract

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.