一系列新型的基于吲唑/吲哚的胰高血糖素受体拮抗剂。
A novel series of indazole-/indole-based glucagon receptor antagonists.
作者信息
Lin Songnian, Zhang Fengqi, Jiang Guoqiang, Qureshi Sajjad A, Yang Xiaodong, Chicchi Gary G, Tota Laurie, Bansal Alka, Brady Edward, Trujillo Maria, Salituro Gino, Miller Corey, Tata James R, Zhang Bei B, Parmee Emma R
机构信息
Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
出版信息
Bioorg Med Chem Lett. 2015 Oct 1;25(19):4143-7. doi: 10.1016/j.bmcl.2015.08.015. Epub 2015 Aug 8.
A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.
发现了一系列新型强效胰高血糖素受体拮抗剂（GRA）。这些基于吲唑和吲哚的化合物是在早期基于吡唑的GRA先导化合物MK-0893的基础上设计的。构效关系（SAR）研究集中在吲唑核心的C3和C6位置，以及吲唑N-1上的苄基位置。鉴定出了多种强效GRA，它们在体外表现优异，在大鼠体内具有良好的药代动力学。其中，GRA 16d在胰高血糖素受体人源化（hGCGR）小鼠的急性胰高血糖素激发模型中，以1、3和10mg/kg（mpk）的剂量口服时，对胰高血糖素诱导的血糖波动具有抑制作用，并且在3mpk剂量下能显著降低hGCGR ob/ob小鼠的急性血糖水平。
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