Discovery of piperazin-1-ylpyridazine-based potent and selective stearoyl-CoA desaturase-1 inhibitors for the treatment of obesity and metabolic syndrome.
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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DOI：
10.1021/jm301661h
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发表时间：
2013-01
影响因子：
7.3
通讯作者：
Zaihui Zhang;Shaoyi Sun;Vishnumurthy Kodumuru;Duanjie Hou;Shifeng Liu;Nagasree Chakka;S. Sviridov;S. Chowdhury;D. McLaren;L. Ratkay;Kuldip Khakh;Xing Cheng;H. Gschwend;R. Kamboj;Jianmin Fu;M. Winther
中科院分区：
文献类型：
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作者：
Zaihui Zhang;Shaoyi Sun;Vishnumurthy Kodumuru;Duanjie Hou;Shifeng Liu;Nagasree Chakka;S. Sviridov;S. Chowdhury;D. McLaren;L. Ratkay;Kuldip Khakh;Xing Cheng;H. Gschwend;R. Kamboj;Jianmin Fu;M. Winther
硬脂酰辅酶a去饱和酶-1 （SCD1）催化饱和脂肪酸从头合成单不饱和脂肪酸。研究表明，缺乏功能性SCD1基因的啮齿动物具有改善的代谢特征，包括体重增加减少、甘油三酯降低和胰岛素反应改善。在这项研究中，我们发现了一系列以哌嗪基吡啶为基础的高效、选择性和口服生物利用度高的化合物。其中，化合物49 （XEN103）具有较高的体外活性(mSCD1 IC（50) = 14 nM, HepG2 IC(50) = 12 nM）和体内有效（ED(50) = 0.8 mg/kg）。在啮齿动物模型中，它也显示出体重增加的显著减少。我们对小分子SCD1抑制剂的研究结果证实了这一靶点在代谢调节中的重要性，描述了评估SCD1抑制剂疗效和耐受性的新模型，并展示了开发代谢性疾病新疗法的机会。
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 IC(50) = 14 nM and HepG2 IC(50) = 12 nM) and efficacious in vivo (ED(50) = 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.