| Literature DB >> 27554445 |
Steven L Kuklish1, Stephen Antonysamy2, Shobha N Bhattachar3, Srinivasan Chandrasekhar3, Matthew J Fisher3, Adrian J Fretland3, Karen Gooding3, Anita Harvey3, Norman E Hughes3, John G Luz2, Peter R Manninen3, James E McGee3, Antonio Navarro3, Bryan H Norman3, Katherine M Partridge3, Steven J Quimby3, Matthew A Schiffler3, Ashley V Sloan3, Alan M Warshawsky3, Jeremy S York3, Xiao-Peng Yu3.
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.Entities:
Keywords: Biomarker; Dog bioavailability; Prostaglandin pathway; mPGES-1
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Year: 2016 PMID： 27554445 DOI： 10.1016/j.bmcl.2016.08.023
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823