Discovery of Potent, Selective, Orally Bioavailable Stearoyl-CoA Desaturase 1 Inhibitors

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• 作者：Gang Liu ; John K. Lynch ; Jennifer Freeman ; Bo Liu ; Zhili Xin ; Hongyu Zhao ; Michael D. Serby ; Philip R. Kym ; Tom S. Suhar ; Harriet T. Smith ; Ning Cao ; Ruojing Yang ; Rich S. Janis ; Joel A. Krauser ; Stev
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：June 28, 2007
• 年：2007
• 卷：50
• 期：13
• 页码：3086 - 3100
• 全文大小：249K
• 年卷期：v.50,no.13(June 28, 2007)
• ISSN：1520-4804

文摘

Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturatedfatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established thatthese animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greaterwhole 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. Therepresentative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion ofsaturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.