Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1

被引：81

作者：

Dow, Robert L. ^{[1
]}

Li, Jian-Cheng ^{[1
]}

Pence, Michael P. ^{[1
]}

Gibbs, E. Michael ^{[1
]}

LaPerle, Jennifer L. ^{[1
]}

Litchfield, John ^{[1
]}

Piotrowski, David W. ^{[1
]}

Munchhof, Michael J. ^{[1
]}

Manion, Tara B. ^{[1
]}

Zavadoski, William J. ^{[1
]}

Walker, Gregory S. ^{[1
]}

McPherson, R. Kirk ^{[1
]}

Tapley, Susan ^{[1
]}

Sugarman, Eliot ^{[1
]}

Guzman-Perez, Angel ^{[1
]}

DaSilva-Jardine, Paul ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Groton, CT 06340 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2011年 / 2卷 / 05期

关键词：

DGAT-1; diabetes; obesity; triglyceride; phototoxicity; acyl glucuronide; COA-DIACYLGLYCEROL ACYLTRANSFERASE-1; OBESITY RESISTANCE; ACYL GLUCURONIDES; METABOLISM; PERMEABILITY; MOLECULE;

D O I：

10.1021/ml200051p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in the biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant to diet-induced obesity and have increased insulin sensitivity. Thus, inhibition of DGAT-1 may represent an attractive target for the treatment of obesity or type II diabetes. Herein, we report the discovery and characterization of a potent and selective DGAT-1 inhibit or PF-04620110 (3). Compound 3 inhibits DGAT-1 with an IC50 of 19 nM and shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of >= 0.1 mg/kg following a lipid challenge. On the basis of this pharmacologic and pharmacokinetic profile, compound 3 has been advanced to human clinical studies.

引用

页码：407 / 412

页数：6

共 26 条

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