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
  • 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.