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Title 

Discovery of a novel class of diacylglycerol acyltransferase 2 inhibitors with a 1H-Pyrrolo[2,3-b]pyridine core

 

DGAT2의 신규 억제물질 발굴

Authors 

Mun-Ock KimSu Ui LeeKwang Man ChoiSangku LeeHyeong Ki KimHyun Ju KangMiri ChoiEun Bin KwonMyung Ji KangSun Hong KimHyun-Jun LeeHyun Sun LeeY S KwakSungchan Cho

Publisher 

Pharmaceutical Society of Japan

Issue Date 

2014

Citation 

Biological & Pharmaceutical Bulletin, vol. 37, no. 10, pp. 1655-1660

Keywords 

Diacylglycerol acyltransferase 2 (DGAT2)Metabolic diseaseSmall molecule inhibitorTriacylglycerol

Abstract 

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. --------------------------------------------------------------------------------

ISSN 

0918-6158

Link 

http://doi.org/10.1248/bpb.b14-00447

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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