Jain Rama, Mathur Michelle, Lan Jiong, Costales Abran, Atallah Gordana, Ramurthy Savithri, Subramanian Sharadha, Setti Lina, Feucht Paul, Warne Bob, Doyle Laura, Basham Stephen, Jefferson Anne B, Appleton Brent A, Lindvall Mika, Shafer Cynthia M
Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
Bioorg Med Chem Lett. 2018 Oct 15;28(19):3197-3201. doi: 10.1016/j.bmcl.2018.08.020. Epub 2018 Aug 21.
Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.
以已描述的3,4-联芳基吡啶系列为起点，引入带有氢键供体和额外疏水接触的第二个环系统，得到了氮杂吲哚系列，该系列表现出强效的、皮摩尔级别的RSK2抑制作用，是迄今为止RSK抑制剂中观察到的最有效的体外靶点调节作用。在更有效的核心结构背景下，对酚部分的几个变化进行了评估，以潜在地找到适合体内评估的工具分子。
