학술논문
Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors.
Document Type
Article
Author
Cernak, Tim; Gesmundo, Nathan J.; Dykstra, Kevin; Yang Yu; Zhicai Wu; Zhi-Cai Shi; Vachal, Petr; Sperbeck, Donald; Shuwen He; Murphy, Beth Ann; Sonatore, Lisa; Williams, Steven; Madeira, Maria; Verras, Andreas; Reiter, Maud; Claire Heechoon Lee; Cuff, James; Sherer, Edward C.; Kuethe, Jeffrey; Goble, Stephen
Source
Subject
*DRUG development
*STRUCTURE-activity relationship in pharmacology
*HIGH throughput screening (Drug development)
*DIGLYCERIDES
*LEAD compounds
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Language
ISSN
0022-2623
Abstract
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 1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging S N Ar 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. [ABSTRACT FROM AUTHOR]