Stephen W. Wright*, Kathleen A. Farley, Seungil Han, John D. Knafels and Katherine L. Lee,
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引用次数: 0
摘要
本文揭示了在发现 IRAK4 抑制剂 Zimlovisertib(PF-06650833)过程中遇到的三种结构-活性关系(SAR)观察结果的根本原因。第一种是异喹啉醚取代基带来的非线性药效 SAR,第二种是氟取代内酰胺带来的药效增强,第三种是氟取代内酰胺对全合成 (2S,3S,4S) 立体化学的轻微药效偏好。我们提供的新数据有助于我们了解这些意想不到的 SAR 趋势的起源。
In Retrospect: Root-Cause Analysis of Structure–Activity Relationships in IRAK4 Inhibitor Zimlovisertib (PF-06650833)
In this paper, we disclose insights on the root causes of three structure–activity relationship (SAR) observations encountered in the discovery of the IRAK4 inhibitor Zimlovisertib (PF-06650833). The first is a nonlinear potency SAR encountered with the isoquinoline ether substituent, the second is a potency enhancement introduced by fluorine substitution on the lactam, and the third is a slight potency preference for all-syn (2S,3S,4S) stereochemistry in the fluorine-substituted lactam. We present new data that help to inform us of the origins of these unexpected SAR trends.
期刊介绍:
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