Design and Optimization of Pyrazinecarboxamide-Based Inhibitors of Diacylglycerol Acyltransferase 1 (DGAT1) Leading to a Clinical Candidate Dimethylpyrazinecarboxamide Phenylcyclohexylacetic Acid (AZD7687)

被引：33

作者：

Barlind, Jonas G. ^{[1
]}

Bauer, Udo A. ^{[1
]}

Birch, Alan M. ^{[2
]}

Birtles, Susan ^{[2
]}

Buckett, Linda K. ^{[2
]}

Butlin, Roger J. ^{[2
]}

Davies, Robert D. M. ^{[2
]}

Eriksson, Jan W. ^{[1
,3
]}

Hammond, Clare D. ^{[2
]}

Hovland, Ragnar ^{[1
]}

Johannesson, Petra ^{[1
]}

Johansson, Magnus J. ^{[1
]}

Kemmitt, Paul D. ^{[2
]}

Lindmark, Bo T. ^{[1
]}

Gutierrez, Pablo Morentin ^{[2
]}

Noeske, Tobias A. ^{[1
]}

Nordin, Andreas ^{[1
]}

O'Donnell, Charles J. ^{[2
]}

Petersson, Annika U. ^{[1
]}

Redzic, Alma ^{[1
]}

Turnbull, Andrew V. ^{[2
]}

Vinblad, Johanna ^{[1
]}

机构：

[1] AstraZeneca R&D, Cardiovasc & Gastrointestinal Innovat Med Unit Mo, S-43183 Molndal, Sweden

[2] AstraZeneca R&D, Macclesfield SK10 4TG, Cheshire, England

[3] Sahlgrens Univ Hosp, Dept Mol & Clin Med, S-41345 Gothenburg, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 23期

关键词：

POTENT; DISCOVERY; OBESITY;

D O I：

10.1021/jm301296t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.

引用

页码：10610 / 10629

页数：20

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