Discovery of Piperazin-1-ylpyridazine-Based Potent and Selective Stearoyl-CoA Desaturase-1 Inhibitors for the Treatment of Obesity and Metabolic Syndrome

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• 作者：Zaihui Zhang ; Shaoyi Sun ; Vishnumurthy Kodumuru ; Duanjie Hou ; Shifeng Liu ; Nagasree Chakka ; Serguei Sviridov ; Sultan Chowdhury ; David G. McLaren ; Leslie G. Ratkay ; Kuldip Khakh ; Xing Cheng ; Heinz W. Gschwend ; Rajender Kamboj ; Jianmin Fu ; Michael D. Winther
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 24, 2013
• 年：2013
• 卷：56
• 期：2
• 页码：568-583
• 全文大小：522K
• 年卷期：v.56,no.2(January 24, 2013)
• ISSN：1520-4804

文摘

Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated fatty acids from saturated fatty acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC₅₀ = 14 nM and HepG2 IC₅₀ = 12 nM) and efficacious in vivo (ED₅₀ = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for metabolic disease.