Design and synthesis of α-aryloxy-α-methylhydrocinnamic acids:: A novel class of dual peroxisome proliferator-activated receptor α/γ agonists

被引：48

作者：

Xu, YP ^{[1
]}

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, S

Winneroski, LL

Zink, R

Kauffman, RF

McCarthy, JR

机构：

[1] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Div A, Indianapolis, IN 46285 USA

[2] Ligand Pharmaceut, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 10期

关键词：

D O I：

10.1021/jm0342616

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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]pheny}-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 (IC50 = 28 and 10 nM; EC50 = 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.

引用

页码：2422 / 2425

页数：4

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