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3,3-二甲基取代的N-芳基哌啶作为强效微粒体前列腺素E合酶-1抑制剂的表征

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

作者信息

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

机构信息

Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.

Eli Lilly Biotechnology Center, San Diego, CA 92121, USA.

出版信息

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

DOI:10.1016/j.bmcl.2016.08.023
PMID:27554445
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.

摘要

在此，我们报告新型、强效的3,3 - 二甲基取代的N - 芳基哌啶类微粒体前列腺素E合酶 - 1（mPGES - 1）抑制剂。在体外人全血（HWB）试验中，实施例14以7nM的IC50有效抑制PGE2合成。此外，14在30μM时对人COX - 1或COX - 2试验无活性，并且在微粒体制备试验中，在62.5μM时未能抑制人mPGES - 2。这些数据与mPGES - 1介导的PGE2选择性降低一致。在犬体内，14的口服生物利用度（74%）、清除率（3.62mL/(min*kg)）和分布容积（Vd,ss = 1.6L/kg）值在我们的目标范围内。基于这些原因，选择14进行进一步研究。

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