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 |
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Authors: | 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 |
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Institution: | WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People’s Republic of China |
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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. |
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Keywords: | DGAT1 Obesity LTT DIO CVUMGQYBAHREIR-JFCQDPQLSA-N |
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