Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists

  • J Med Chem. 2004 May 6;47(10):2422-5. doi: 10.1021/jm0342616.
Yanping Xu  1 ,  Christopher J Rito ,  Garret J Etgen ,  Robert J Ardecky ,  James S Bean ,  William R Bensch ,  Jacob R Bosley ,  Carol L Broderick ,  Dawn A Brooks ,  Samuel J Dominianni ,  Patric J Hahn ,  Sha Liu ,  Dale E Mais ,  Chahrzad Montrose-Rafizadeh ,  Kathy M Ogilvie ,  Brian A Oldham ,  Mary Peters ,  Deepa K Rungta ,  Anthony J Shuker ,  Gregory A Stephenson ,  Allie E Tripp ,  Sarah B Wilson ,  Leonard L Winneroski ,  Richard Zink ,  Raymond F Kauffman ,  James R McCarthy
Affiliations
  • 1. Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. [email protected]
PMID: 15115385 DOI: 10.1021/jm0342616
Abstract

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves Insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.