2. Academic Validation
  3. Synthesis and biological evaluation of novel pyrrolidine acid analogs as potent dual PPARα/γ agonists

Synthesis and biological evaluation of novel pyrrolidine acid analogs as potent dual PPARα/γ agonists

  • Bioorg Med Chem Lett. 2015 Mar 15;25(6):1196-205. doi: 10.1016/j.bmcl.2015.01.066.
Hao Zhang 1,  Charles Z Ding 1,  Zhi Lai 1,  Sean S Chen 1,  Pratik Devasthale 1,  Tim Herpin 1,  George Morton 1,  Fucheng Qu 1,  Denis Ryono 1,  Rebecca Smirk 1,  Wei Wang 1,  Shung Wu 1,  Xiang-Xang Ye 1,  Yi-Xin Li 2,  Atsu Apedo 2,  Dennis Farrelly 3,  Tao Wang 4,  Liqun Gu 3,  Nathan Morgan 3,  Neil Flynn 3,  Cuixia Chu 3,  Lori Kunselman 3,  Jonathan Lippy 4,  Kenneth Locke 4,  Kevin O'Malley 4,  Thomas Harrity 3,  Michael Cap 3,  Lisa Zhang 5,  Vinayak Hosagrahara 5,  Pathanjali Kadiyala 5,  Carrie Xu 5,  Arthur M Doweyko 6,  Robert Zahler 1,  Narayanan Hariharan 3,  Peter T W Cheng 1
Affiliations

Affiliations

  • 1 Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development (R&D), Princeton, NJ 08543-5400, USA.
  • 2 Discovery Analytical Sciences, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
  • 3 Metabolic Diseases Biology, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
  • 4 Lead Evaluation, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
  • 5 Metabolism and Pharmacokinetics, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
  • 6 Computer-Assisted Drug Design, Bristol-Myers Squibb R&D, Princeton, NJ 08543-5400, USA.
PMID: 25686852 DOI: 10.1016/j.bmcl.2015.01.066
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-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 efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.

Keywords

Dual agonists; Peroxisome Proliferator-Activated Receptor; Pyrrolidine acid; Type 2 diabetes.

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