Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors

被引：57

作者：

Cernak, Tim ^{[1
]}

Gesmundo, Nathan J. ^{[1
]}

Dykstra, Kevin ^{[1
]}

Yu, Yang ^{[1
]}

Wu, Zhicai ^{[1
]}

Shi, Zhi-Cai ^{[1
]}

Vachal, Petr ^{[1
]}

Sperbeck, Donald ^{[1
]}

He, Shuwen ^{[1
]}

Murphy, Beth Ann ^{[1
]}

Sonatore, Lisa ^{[1
]}

Williams, Steven ^{[1
]}

Madeira, Maria ^{[1
]}

Verras, Andreas ^{[1
]}

Reiter, Maud ^{[1
]}

Lee, Claire Heechoon ^{[1
]}

Cuff, James ^{[1
]}

Sherer, Edward C. ^{[1
]}

Kuethe, Jeffrey ^{[1
]}

Goble, Stephen ^{[1
]}

Perrotto, Nicholas ^{[1
]}

Pinto, Shirly ^{[1
]}

Shen, Dong-Ming ^{[1
]}

Nargund, Ravi ^{[1
]}

Balkovec, James ^{[1
]}

DeVita, Robert J. ^{[1
]}

Dreher, Spencer D. ^{[1
]}

机构：

[1] Merck & Co Inc, MRL, Dept Discovery Chem, Rahway, NJ 07065 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 09期

关键词：

LATE-STAGE FUNCTIONALIZATION; MEDICINAL CHEMISTS TOOLBOX; DGAT1; INHIBITORS; ARYL CHLORIDES; HYDROGENATION; OPTIMIZATION; MECHANISM; BASE;

D O I：

10.1021/acs.jmedchem.6b01543

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on similar to 1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

引用

页码：3594 / 3605

页数：12

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