Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-d]pyrimidine core

被引：18

作者：

Dow, Robert L. ^{[1
]}

Andrews, Melissa ^{[1
]}

Aspnes, Gary E. ^{[1
]}

Balan, Gayatri ^{[1
]}

Gibbs, E. Michael ^{[1
]}

Guzman-Perez, Angel ^{[1
]}

Karki, Kapil ^{[1
]}

LaPerle, Jennifer L. ^{[1
]}

Li, Jian-Cheng ^{[1
]}

Litchfield, John ^{[1
]}

Munchhof, Michael J. ^{[1
]}

Perreault, Christian ^{[1
]}

Patel, Leena ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 20期

关键词：

DGAT-1; Inhibition; Dioxino[2,3-d]pyrimidine; Obesity; Diabetes; Triglycerides; IDENTIFICATION; METABOLISM;

D O I：

10.1016/j.bmcl.2011.08.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of potent DGAT-1 inhibitors was developed originating from the lactam-based clinical candidate PF-04620110. Incorporation of a dioxino[2,3-d]pyrimidine-based core afforded good alignment of pharmacophore features and resulted in improved passive permeability. Development of an efficient, homochiral synthesis of these targets facilitated confirmation of predictions regarding the stereochemical-dependence of DGAT-1 inhibition for this series. Compound 10 was shown to be a potent inhibitor of human DGAT-1 (10 nM) and to suppress triglyceride synthesis at oral doses of <3 mg/kg. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6122 / 6125

页数：4

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