Discovery of dimethyl pent-4-ynoic acid derivatives, as potent and orally bioavailable DGAT1 inhibitors that suppress body weight in diet-induced mouse obesity model

Tao Yu; Chengde Wu; NengYang Shih; Qi Li; Chichung Chan; He Pan; Dan Yao; Yan Pan; Wei Liang; Liang Shen; Hui Zhao; Jian Li; Shuhui Chen

doi:10.1016/j.bmcl.2018.04.051

Discovery of dimethyl pent-4-ynoic acid derivatives, as potent and orally bioavailable DGAT1 inhibitors that suppress body weight in diet-induced mouse obesity model

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1686-1692. doi: 10.1016/j.bmcl.2018.04.051. Epub 2018 Apr 21.

Authors

Tao Yu¹, Chengde Wu², NengYang Shih², Qi Li², Chichung Chan², He Pan², Dan Yao², Yan Pan², Wei Liang², Liang Shen², Hui Zhao², Jian Li², Shuhui Chen²

Affiliations

¹ WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China. Electronic address: yu_tao_001391@wuxiapptec.com.
² WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.

PMID: 29699923
DOI: 10.1016/j.bmcl.2018.04.051

Abstract

Diacylglycerol acyltransferase (DGAT) is expressed abundantly in intestine, liver, and adipose tissues. DGAT1 is the crucial and rate-limiting enzyme that mediates the final step in triacylglycerol (TAG) resynthesis during dietary fat absorption. However, too much triacylglycerol (TAG) reserve will lead to genetic obesity (Hubert et al., 2000). DGAT1 knockout mice could survive and displayed a reduction in the postprandial rise of plasma TG, and increased sensitivity of insulin and leptin. Here we report the discovery and characterization of a novel selective DGAT1 inhibitor 29 to potentially treat obesity. Compound 29 showed lipid lowering effect in mouse lipid tolerance test (LTT) and also reduced body weight in DIO mice without observable liver damage.

Keywords: DGAT1; DIO; LTT; Obesity.

MeSH terms

Administration, Oral
Amino Acids, Aromatic
Animals
Biological Availability
Body Weight / drug effects
Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
Diacylglycerol O-Acyltransferase / deficiency
Diacylglycerol O-Acyltransferase / metabolism
Dietary Fats / adverse effects*
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Fatty Acids, Unsaturated / administration & dosage
Fatty Acids, Unsaturated / chemistry
Fatty Acids, Unsaturated / pharmacology*
HEK293 Cells
Humans
Mice
Mice, Knockout
Molecular Structure
Obesity / drug therapy*
Obesity / metabolism
Structure-Activity Relationship

Substances

2-amino-5-(4-fluorophenyl)pent-4-ynoic acid
Amino Acids, Aromatic
Dietary Fats
Enzyme Inhibitors
Fatty Acids, Unsaturated
4-pentynoic acid
DGAT1 protein, human
Diacylglycerol O-Acyltransferase