Liu Gang, Lynch John K, Freeman Jennifer, Liu Bo, Xin Zhili, Zhao Hongyu, Serby Michael D, Kym Philip R, Suhar Tom S, Smith Harriet T, Cao Ning, Yang Ruojing, Janis Rich S, Krauser Joel A, Cepa Steven P, Beno David W A, Sham Hing L, Collins Christine A, Surowy Teresa K, Camp Heidi S
Metabolic Disease Research, Drug Metabolism, Advanced Technology, Exploratory Pharmacokinetics, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6101, USA.
J Med Chem. 2007 Jun 28;50(13):3086-100. doi: 10.1021/jm070219p. Epub 2007 May 27.
Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.
硬脂酰辅酶A去饱和酶1（SCD1）催化饱和长链脂肪酸生物合成单不饱和脂肪酸的关键步骤。对SCD1基因敲除小鼠的研究表明，这些动物体型瘦，可免受瘦素缺乏诱导和饮食诱导的肥胖影响，全身胰岛素敏感性高于野生型动物。在本研究中，我们基于已知的哒嗪甲酰胺模板发现了一系列强效、选择性、口服生物可利用的SCD1抑制剂。代表性先导抑制剂28c在HepG2细胞中阻断饱和长链脂肪酸辅酶A（LCFA-CoAs）转化为单不饱和LCFA-CoAs方面也表现出优异的细胞活性。
