Design and synthesis of novel and potent amide linked PPARgamma/delta dual agonists

  • Bioorg Med Chem Lett. 2007 Dec 15;17(24):6744-9. doi: 10.1016/j.bmcl.2007.10.047.
Qing Shi  1 ,  Emily J Canada ,  Yanping Xu ,  Alan M Warshawsky ,  Garret J Etgen ,  Carol L Broderick ,  Cathleen K Clutinger ,  Lynnie A Irwin ,  Michael E Laurila ,  Chahrzad Montrose-Rafizadeh ,  Brian A Oldham ,  Minmin Wang ,  Leonard L Winneroski ,  Chaoyu Xie ,  Jeremy S York ,  Nathan P Yumibe ,  Richard W Zink ,  Nathan Mantlo
Affiliations
  • 1. Eli Lilly and Company, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285, USA. [email protected]
PMID: 18029178 DOI: 10.1016/j.bmcl.2007.10.047
Abstract

A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.