Xu Jiayi, Lin Songnian, Myers Robert W, Addona George, Berger Joel P, Campbell Brian, Chen Hsuan-Shen, Chen Zhesheng, Eiermann George J, Elowe Nadine H, Farrer Brian T, Feng Wen, Fu Qinghong, Kats-Kagan Roman, Kavana Michael, Malkani Sunita, McMasters Daniel R, Mitra Kaushik, Pachanski Michele J, Tong Xinchun, Trujillo Maria E, Xu Libo, Zhang Bei, Zhang Fengqi, Zhang Rui, Parmee Emma R
Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
Discovery, Preclinical and Early Development, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ, USA.
Bioorg Med Chem Lett. 2017 May 1;27(9):2069-2073. doi: 10.1016/j.bmcl.2016.10.085. Epub 2016 Oct 31.
Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic β-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.
葡萄糖激酶（GK，己糖激酶IV）是一种独特的己糖激酶，在哺乳动物葡萄糖稳态中起核心作用。胰腺β细胞中GK介导的葡萄糖磷酸化是控制葡萄糖刺激的胰岛素分泌的限速步骤。同样，肝细胞中GK介导的葡萄糖磷酸化在增加肝脏葡萄糖摄取和代谢以及可能降低肝脏葡萄糖输出方面起主要作用。已鉴定出通过与变构位点结合来增加酶活性的小分子GK激活剂（GKA）。GKA为2型糖尿病（T2DM）的治疗提供了一种新方法，因此备受关注。我们现在报告一系列新型2,5,6-三取代吲哚衍生物的设计、合成及生物学评价，这些衍生物是高效的GKA。其中，化合物1在体外具有高效力、优异的物理化学性质以及在啮齿动物中良好的药代动力学特征。在3周高脂饮食喂养的小鼠中，以低至0.03mg/kg的剂量口服化合物1导致显著的血糖降低效果。
