新型酰基辅酶 A（CoA）：二酰基甘油酰基转移酶-1 抑制剂：二酰基乙二胺衍生物的合成与生物学活性。

Novel acyl coenzyme A (CoA): diacylglycerol acyltransferase-1 inhibitors: synthesis and biological activities of diacylethylenediamine derivatives.

机构信息

Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.

出版信息

Bioorg Med Chem. 2010 Apr 1;18(7):2785-95. doi: 10.1016/j.bmc.2010.01.067. Epub 2010 Feb 4.

DOI:10.1016/j.bmc.2010.01.067

PMID:20207151

Abstract

A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight.

摘要

一系列二酰基乙二胺衍生物被合成并评估了它们对 DGAT-1 的抑制活性和药代动力学特征，以发现新的小分子 DGAT-1 抑制剂。在这些化合物中，N-[2-({[1-苯基-3-(三氟甲基)-1H-吡唑-4-基]羰基}氨基)乙基]-6-(2,2,2-三氟乙氧基)吡啶-3-甲酰胺 3x 表现出很强的抑制活性和优异的 PK 特征。3x 经口给予饮食诱导肥胖的小鼠，可降低体重增加和白色脂肪组织重量。