Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors

被引：106

作者：

Haffner, Curt D. ^{[1
]}

Becherer, J. David ^{[1
]}

Boros, Eric E. ^{[1
]}

Cadilla, Rodolfo ^{[1
]}

Carpenter, Tiffany ^{[1
]}

Cowan, David ^{[1
]}

Deaton, David N. ^{[1
]}

Guo, Yu ^{[1
]}

Harrington, Wallace ^{[1
]}

Henke, Brad R. ^{[1
]}

Jeune, Michael R. ^{[1
]}

Kaldor, Istvan ^{[1
]}

Milliken, Naphtali ^{[1
]}

Petrov, Kim G. ^{[1
]}

Preugschat, Frank ^{[1
]}

Schulte, Christie ^{[1
]}

Shearer, Barry G. ^{[1
]}

Shearer, Todd ^{[1
]}

Smalley, Terrence L., Jr. ^{[1
]}

Stewart, Eugene L. ^{[1
]}

Stuart, J. Darren ^{[1
]}

Ulrich, John C. ^{[1
]}

机构：

[1] GlaxoSmithKline, Res & Dev, Res Triangle Pk, NC 27709 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 08期

关键词：

CELL-DEATH; ANALOGS; NAD(+); FAMILY; METABOLISM; DESIGN; TARGET;

D O I：

10.1021/jm502009h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.

引用

页码：3548 / 3571

页数：24

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