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

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• 作者：Steven L. Kuklish^a ; ^{Kuklish_Steven@lilly.com" class="auth_mail" title="E-mail the corresponding author} ; Stephen Antonysamy^b ; Shobha N. Bhattachar^a ; Srinivasan Chandrasekhar^a ; ^&dagger ; ; Matthew J. Fisher^a ; Adrian J. Fretland^a ; ^&Dagger ; ; Karen Gooding^a ; ^&dagger ; ; Anita Harvey^a ; ^&dagger ; ; Norman E. Hughes^a ; John G. Luz^b ; Peter R. Manninen^a ; James E. McGee^a ; Antonio Navarro^a ; Bryan H. Norman^a ; Katherine M. Partridge^a ; Steven J. Quimby^a ; Matthew A. Schiffler^a ; Ashley V. Sloan^a ; Alan M. Warshawsky^a ; Jeremy S. York^a ; Xiao-Peng Yu^a
• 关键词：mPGES-1 ; Prostaglandin pathway ; Dog bioavailability ; Biomarker
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：26
• 期：19
• 页码：4824-4828
• 全文大小：2442 K

文摘

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 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.