Discovery of potent, selective, orally bioavailable stearoyl-CoA desaturase 1 inhibitors |
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Authors: | 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 |
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Affiliation: | Metabolic Disease Research, Drug Metabolism, Advanced Technology, Exploratory Pharmacokinetics, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6101, USA. liugx@gmail.com |
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Abstract: | 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. |
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