作为选择性 AKT 抑制剂的 2,3,5-三取代吡啶。第二部分：从氮茚并咪唑改善的类药性和激酶选择性。
2,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles.
机构信息
Oncology Medicinal Chemistry, GlaxoSmithKline,1250 S. Collegeville, Rd., Collegeville, PA 19426, United States.
出版信息
Bioorg Med Chem Lett. 2010 Jan 15;20(2):679-83. doi: 10.1016/j.bmcl.2009.11.060. Epub 2009 Nov 20.
PMID:20005102
Abstract
A novel series of AKT inhibitors containing 2,3,5-trisubstituted pyridines with novel azaindazoles as hinge binding elements are described. Among these, the 4,7-diazaindazole compound 2c has improved drug-like properties and kinase selectivity than those of indazole 1, and displays greater than 80% inhibition of GSK3beta phosphorylation in a BT474 tumor xenograft model in mice.
摘要
本文描述了一系列新型的 AKT 抑制剂，它们含有 2,3,5-三取代的吡啶，并将新型的氮杂吲哚作为铰链结合基团。在这些化合物中，4,7-二氮杂吲哚化合物 2c 具有比吲哚 1 更好的类药性和激酶选择性，并在 BT474 肿瘤异种移植模型的小鼠中显示出大于 80%的 GSK3β 磷酸化抑制作用。
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