Accelerating the discovery of DGAT1 inhibitors through the application of parallel medicinal chemistry (PMC)

被引：7

作者：

Yu, Yang ^{[1
]}

Wu, Zhicai ^{[1
]}

Shi, Zhi-Cai ^{[1
]}

He, Shuwen ^{[1
]}

Lai, Zhong ^{[1
]}

Cernak, Timothy A. ^{[1
]}

Vachal, Petr ^{[1
]}

Liu, Min ^{[1
]}

Liu, Jian ^{[1
]}

Hong, Qingmei ^{[1
]}

Jian, Tianying ^{[1
]}

Guiadeen, Deodial ^{[1
]}

Krikorian, Arto ^{[1
]}

Sperbeck, Donald M. ^{[1
]}

Verras, Andreas ^{[1
]}

Sonatore, Lisa M. ^{[1
]}

Murphy, Beth A. ^{[1
]}

Wiltsie, Judyann ^{[1
]}

Chung, Christine C. ^{[1
]}

Gorski, Judith N. ^{[1
]}

Liu, Jinqi ^{[1
]}

Xiao, Jianying ^{[1
]}

Wolff, Michael ^{[1
]}

Tong, Sharon X. ^{[1
]}

Madeira, Maria ^{[1
]}

Karanam, Bindhu, V ^{[1
]}

Shen, Dong-Ming ^{[1
]}

Balkovec, James M. ^{[1
]}

De Vita, Robert J. ^{[1
]}

Pinto, Shirly ^{[1
]}

Nargund, Ravi P. ^{[1
]}

机构：

[1] Merck & Co Inc, Discovery & Preclin Sci, 2000 Galloping Hill Rd, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 11期

关键词：

Parallel medicinal chemistry; High throughput purification; DGAT1; inhibitor; Triglyceride; Benzimidazole; ACAT1; A2A receptor; Cyclohexane acetic acid; Lipid tolerance test; Pharmacokinetics; HEALTH-CARE PROFESSIONALS; RESEARCH-AND-DEVELOPMENT; DIACYLGLYCEROL ACYLTRANSFERASE; DRUG DISCOVERY; POTENT; STATEMENT; DISEASE;

D O I：

10.1016/j.bmcl.2019.03.039

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

引用

页码：1380 / 1385

页数：6

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