The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead 2f bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with 2f. By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we improved the preclinical species PK and solubility and reduced adenosine uptake activity. The excellent potency and kinome selectivity of 7-azaoxindole 4d and spirooxindole 5d, together with a low plasma clearance and good half-life in rat and dog, supported a low once-daily predicted human dose.

中文翻译：

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优化作为选择性 PI3Kδ 抑制剂的多功能氧化吲哚

3,3-二取代的oxindole 部分是一种多功能且刚性的三维形状支架。当设计有嘌呤铰链结合核心时，通过利用同种型选择性口袋的微小差异发现了具有异常选择性的 PI3Kδ 激酶抑制剂。早期铅2f与 PI3Kδ 和 PI3Kα 结合的晶体结构有助于使2f观察到的高选择性合理化。通过减弱羟吲哚部分的亲脂性和代谢倾向，我们提高了临床前物种的 PK 和溶解度，并降低了腺苷摄取活性。7-azaoxindole 4d和spirooxindole 5d的优异效价和激酶组选择性，加上在大鼠和狗中较低的血浆清除率和良好的半衰期，支持每日一次预测的低人用剂量。