Discovery of a Potent, Selective, and Orally Efficacious Pyrimidinooxazinyl Bicyclooctaneacetic Acid Diacylglycerol Acyltransferase-1 Inhibitor

被引：63

作者：

Birch, Alan M. ^{[1
]}

Birtles, Susan ^{[1
]}

Buckett, Linda K. ^{[1
]}

Kemmitt, Paul D. ^{[1
]}

Smith, Graham J. ^{[1
]}

Smith, Tim J. D. ^{[1
]}

Turnbull, Andrew V. ^{[1
]}

Wang, Steven J. Y. ^{[1
]}

机构：

[1] AstraZeneca, Mereside, Macclesfield SK10 4TG, Cheshire, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 06期

关键词：

OBESITY;

D O I：

10.1021/jm801507v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of DGAT-1 is increasingly seen as an attractive mechanism with the potential for treatment of obesity and other elements of the metabolic syndrome. We report here a bicyclooctaneacetic acid derivative in the pyrimidinooxazine structural class of DGAT-1 inhibitors that has good potency, selectivity, and pharmacokinetic characteristics across a variety of species. This compound is an effective inhibitor of DGAT-1 in both intestinal and adipose tissue, which results in a reduction in body weight or body weight gain following oral administration in both mouse and rat models of dietary-induced obesity.

引用

页码：1558 / 1568

页数：11

共 22 条

[1] ALDRICH PE, 1969, Patent No. 1812906
[2] NEW METHODS AND REAGENTS IN ORGANIC-SYNTHESIS .8. TRIMETHYLSILYLDIAZOMETHANE, A NEW, STABLE, AND SAFE REAGENT FOR THE CLASSICAL ARNDT-EISTERT SYNTHESIS
AOYAMA, T
SHIOIRI, T
[J]. TETRAHEDRON LETTERS, 1980, 21 (46) : 4461 - 4462
[3] BILLHEIMER JT, 1985, METHOD ENZYMOL, V111, P286
[4] Obesity: The disease
Bray, George A.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (14) : 4001 - 4007
[5] Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis
Cases, S
Smith, SJ
Zheng, YW
Myers, HM
Lear, SR
Sande, E
Novak, S
Collins, C
Welch, CB
Lusis, AJ
Erickson, SK
Farese, RV
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (22) : 13018 - 13023
[6] PREPARATION OF 4-SUBSTITUTED 1-METHOXYCARBONYLBICYCLO 2.2.2!OCTANES, SUBSTITUTED 1-PHENYLBICYCLO 2.2.2!OCTANES, 4-SUBSTITUTED 1-PARA-NITROPHENYLBICYCLO 2.2.2!OCTANES, AND 1,4-DISUBSTITUTED BICYCLO 2.2.2!OCTANES
CHAPMAN, NB
SOTHEESW.S
TOYNE, KJ
[J]. JOURNAL OF ORGANIC CHEMISTRY, 1970, 35 (04) : 917 - &
[7] Inhibition of triglyceride synthesis as a treatment strategy for obesity - Lessons from DGAT1-deficient mice
Chen, HC
Farese, RV
[J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (03) : 482 - 486
[8] COLEMAN RA, 1992, METHOD ENZYMOL, V209, P98
[9] Ebner T, 1999, DRUG METAB DISPOS, V27, P1143
[10] Fox BM, 2004, Patent No. 2004047755

← 1 2 3 →