Synthesis and biological evaluation of novel pyrrolidine acid analogs as potent dual PPARα/γ agonists
作者:Hao Zhang、Charles Z. Ding、Zhi Lai、Sean S. Chen、Pratik Devasthale、Tim Herpin、George Morton、Fucheng Qu、Denis Ryono、Rebecca Smirk、Wei Wang、Shung Wu、Xiang-Xang Ye、Yi-Xin Li、Atsu Apedo、Dennis Farrelly、Tao Wang、Liqun Gu、Nathan Morgan、Neil Flynn、Cuixia Chu、Lori Kunselman、Jonathan Lippy、Kenneth Locke、Kevin O’Malley、Thomas Harrity、Michael Cap、Lisa Zhang、Vinayak Hosagrahara、Pathanjali Kadiyala、Carrie Xu、Arthur M. Doweyko、Robert Zahler、Narayanan Hariharan、Peter T.W. Cheng
DOI:10.1016/j.bmcl.2015.01.066
日期:2015.3
design, synthesis and structure–activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was
概述了新型3,4-二取代吡咯烷酸类似物作为PPAR配体的设计,合成和结构-活性关系。在1,3-和1,4-氧苄基吡咯烷酸系列中,优选的立体化学显示为顺式-3 R,4 S异构体,如有效的双重PPARα/γ激动剂3k和4i所示。所述Ñ -4-三氟甲基-嘧啶基吡咯烷类似物4I是在糖尿病降低空腹血糖和甘油三酯水平有效分贝/分贝小鼠。