Synthesis and biological evaluation of novel pyrrolidine acid analogs as potent dual PPARα/γ agonists. Issue 6 (15th March 2015)

• Record Type: Journal Article
• Authors: Zhang, Hao; Ding, Charles Z.; Lai, Zhi; Chen, Sean S.; Devasthale, Pratik; Herpin, Tim; Morton, George; Qu, Fucheng; Ryono, Denis; Smirk, Rebecca; Wang, Wei; Wu, Shung; Ye, Xiang-Xang; Li, Yi-Xin; Apedo, Atsu; Farrelly, Dennis; Wang, Tao; Gu, Liqun; Morgan, Nathan; Flynn, Neil; Chu, Cuixia; Kunselman, Lori; Lippy, Jonathan; Locke, Kenneth; O'Malley, Kevin; Harrity, Thomas; Cap, Michael; Zhang, Lisa; Hosagrahara, Vinayak; Kadiyala, Pathanjali; Xu, Carrie; Doweyko, Arthur M.; Zahler, Robert; Hariharan, Narayanan; Cheng, Peter T.W.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 6(2015)
• Page Start: 1196
• Page End: 1205
• Publication Date: 2015-03-15
• Subjects: Peroxisome Proliferator-Activated Receptor -- Dual agonists -- Pyrrolidine acid -- Type 2 diabetes; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.01.066
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The 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 -3 R, 4 S isomer, as exemplified by the potent dual PPARα/γ agonists3k and4i . The N -4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db / db mice.