Discovery of substituted 3H-pyrido[2,3-d]pyrimidin-4-ones as potent, biased, and orally bioavailable sst2 agonist
作者:Jian Zhao、Zhiyong Chen、Ana Karin Kusnetzow、Julie Nguyen、Elizabeth Rico-Bautista、Hannah Tan、Stephen F. Betz、R. Scott Struthers、Yunfei Zhu
DOI:10.1016/j.bmcl.2020.127496
日期:2020.11
The discovery of a novel 3H-pyrido[2,3-d]pyrimidin-4-one series as potent and biased sst2 agonists is described. This class of molecules exhibits excellent sst2 potency and selectivity against sst1, sst3, and sst5 receptors, and they are significantly more potent at inhibiting cAMP production than inducing internalization. The orally bioavailable 6-(3-chloro-5-methylphenyl)-3-(3-fluoro-5-hydroxyph
描述了新型3 H-吡啶并[2,3-d]嘧啶-4-酮系列作为有效和偏向的sst2激动剂的发现。这类分子对sst1,sst3和sst5受体表现出出色的sst2效能和选择性,与抑制内在作用相比,它们在抑制cAMP产生上的作用明显更强。口服生物可用的6-(3-氯-5-甲基苯基)-3-(3-氟-5-羟基苯基)-5-(甲基[(2 S)-吡咯烷基-2-基甲基]氨基}甲基)-3 H,4 H-吡啶并[2,3-d]嘧啶-4-酮(36)也以剂量依赖性方式抑制GHRH攻击的大鼠中的GH分泌。