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新型噻吩嘧啶衍生物的合成与生物评价作为二酰基甘油酰基转移酶 1（DGAT-1）抑制剂。

Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors.

机构信息

College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.

Hanmi Research Center, Hanmi Pharm. Co., Ltd., Gyeonggi-Do, Republic of Korea.

出版信息

J Enzyme Inhib Med Chem. 2020 Dec;35(1):227-234. doi: 10.1080/14756366.2019.1693555.

DOI:10.1080/14756366.2019.1693555
PMID:31752563
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6882492/
Abstract

A novel series of thieno[3,2-]pyrimidine derivatives were synthesised and their inhibitory effects against diacylglycerol acyltransferase 1 (DGAT-1) were assessed. cis-Isomer showed potent and selective inhibitory activity against DGAT-1 in SF9 cells. In addition, had an acceptable pharmacokinetic profile and accumulated mainly in the small intestine and liver. Oral administration of led to a significant reduction in plasma triacylglycerol level during an oral lipid tolerance test (OLTT) in murine and canine models. Taken together, is a high-quality candidate that deserves further investigation.

摘要

我们合成了一系列新型噻吩并[3,2-b]嘧啶衍生物，并评估了它们对二酰基甘油酰基转移酶 1（DGAT-1）的抑制作用。顺式异构体在 SF9 细胞中对 DGAT-1 表现出强大且选择性的抑制活性。此外，化合物 在药代动力学方面表现出可接受的特性，主要在小肠和肝脏中积累。在小鼠和犬模型的口服脂质耐量试验（OLTT）中，口服给予 可显著降低血浆三酰甘油水平。综上所述， 是一种很有前途的候选药物，值得进一步研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/46d59013a25c/IENZ_A_1693555_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/dfb25f9c1441/IENZ_A_1693555_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/451c54c09de9/IENZ_A_1693555_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/cb196ee1daab/IENZ_A_1693555_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/60a2593845f2/IENZ_A_1693555_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/7d62ee71b287/IENZ_A_1693555_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/3196fa03c7a4/IENZ_A_1693555_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/46d59013a25c/IENZ_A_1693555_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/dfb25f9c1441/IENZ_A_1693555_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/451c54c09de9/IENZ_A_1693555_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/cb196ee1daab/IENZ_A_1693555_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/60a2593845f2/IENZ_A_1693555_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/7d62ee71b287/IENZ_A_1693555_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/3196fa03c7a4/IENZ_A_1693555_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e57/6882492/46d59013a25c/IENZ_A_1693555_F0005_C.jpg

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Role of DGAT enzymes in triacylglycerol metabolism.
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