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. 2016 Oct 1;26(19):4824-4828.
doi: 10.1016/j.bmcl.2016.08.023. Epub 2016 Aug 10.

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors

Steven L Kuklish  1 , Stephen Antonysamy  2 , Shobha N Bhattachar  3 , Srinivasan Chandrasekhar  3 , Matthew J Fisher  3 , Adrian J Fretland  3 , Karen Gooding  3 , Anita Harvey  3 , Norman E Hughes  3 , John G Luz  2 , Peter R Manninen  3 , James E McGee  3 , Antonio Navarro  3 , Bryan H Norman  3 , Katherine M Partridge  3 , Steven J Quimby  3 , Matthew A Schiffler  3 , Ashley V Sloan  3 , Alan M Warshawsky  3 , Jeremy S York  3 , Xiao-Peng Yu  3
Affiliations

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors

Steven L Kuklish et al. Bioorg Med Chem Lett. .

Abstract

Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30μM, and failed to inhibit human mPGES-2 at 62.5μM 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 (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.

Keywords: Biomarker; Dog bioavailability; Prostaglandin pathway; mPGES-1.

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