Document Report Card

ID: ALA1148303

Journal: J Med Chem

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

Authors: Xu Y, Rito CJ, Etgen GJ, Ardecky RJ, Bean JS, Bensch WR, Bosley JR, Broderick CL, Brooks DA, Dominianni SJ, Hahn PJ, Liu S, Mais DE, Montrose-Rafizadeh C, Ogilvie KM, Oldham BA, Peters M, Rungta DK, Shuker AJ, Stephenson GA, Tripp AE, Wilson SB, Winneroski LL, Zink R, Kauffman RF, McCarthy JR.

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.

CiteXplore: 15115385

DOI: 10.1021/jm0342616