Discovery of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors with a 1H-Pyrrolo[2,3-b]pyridine Core

作者：Kim Mun Ock; Lee Suui; Choi Kwangman; Lee Sangku; Kim Hyeongki; Kang Hyunju; Choi Miri; Kwon Eun Bin; Kang Myung Ji; Kim Sunhong; Lee Hyun Jun; Lee Hyun Sun; Kwak Young Shin^*; Cho Sungchan

来源：Biological & Pharmaceutical Bulletin, 2014, 37(10): 1655-1660.

• metabolic disease
• triacylglycerol
• diacylglycerol acyltransferase 2 (DGAT2)
• small molecule inhibitor

Diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step in triacylglycerol (TG) synthesis, is a key enzyme associated with hepatic steatosis and insulin resistance. Here, using an in vitro screen of 20000 molecules, we identified a class of compounds with a substituted 1H-pyrrolo[2,3-b]pyridine core which proved to be potent and selective inhibitors of human DGAT2. Of these compounds, H2-003 and -005 exhibited a considerable reduction in TG biosynthesis in HepG2 hepatic cells and 3T3-L1 preadipose cells. These compounds exert DGAT2-specific-inhibitory activity, which was further confirmed in DGAT2- or DGAT1-overexpressing HEK293 cells. In addition, these compounds almost completely abolished lipid droplet formation in 3T3-L1 cells when co-treated with a DGAT1 inhibitor, which was not attained using either a DGAT2 or DGAT1 inhibitor alone. Collectively, we identified two DGAT2 inhibitors, H2-003 and -005. These compounds will aid in DGAT2-related lipid metabolism research as well as in therapeutic development for the treatment of metabolic diseases associated with excessive TG.

• 出版日期2014-10