Design and synthesis of dual peroxisome proliferator-activated receptors gamma and delta agonists as novel euglycemic agents with a reduced weight gain profile

  • J Med Chem. 2006 Sep 21;49(19):5649-52. doi: 10.1021/jm060617c.
Yanping Xu  1 ,  Garret J Etgen ,  Carol L Broderick ,  Emily Canada ,  Isabel Gonzalez ,  Jason Lamar ,  Chahrzad Montrose-Rafizadeh ,  Brian A Oldham ,  John J Osborne ,  Chaoyu Xie ,  Qing Shi ,  Leonard L Winneroski ,  Jeremy York ,  Nathan Yumibe ,  Richard Zink ,  Nathan Mantlo
Affiliations
  • 1. Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. [email protected]
PMID: 16970391 DOI: 10.1021/jm060617c
Abstract

The design and synthesis of the dual Peroxisome Proliferator-activated Receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves Insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.