Discovery of potent, selective, orally bioavailable stearoyl-CoA desaturase 1 inhibitors.

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.

发现有效的、选择性的、口服生物可利用的硬脂酰辅酶a去饱和酶1抑制剂。

硬脂酰辅酶a去饱和酶1 (SCD1)催化从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已经证实，这些动物是瘦的，不受瘦素缺乏诱导的和饮食诱导的肥胖的影响，比野生型动物具有更高的全身胰岛素敏感性。在这项工作中，我们发现了一系列基于已知哒嗪甲酰胺模板的有效、选择性、口服生物利用的SCD1抑制剂。代表性的铅抑制剂28c也证明了在HepG2细胞中阻断饱和长链脂肪酸辅酶a(LCFA 辅酶a)转化为单不饱和LCFA 辅酶a的优异细胞活性。