In Retrospect: Root-Cause Analysis of Structure–Activity Relationships in IRAK4 Inhibitor Zimlovisertib (PF-06650833)

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-03-21 DOI:10.1021/acsmedchemlett.4c00036

Stephen W. Wright*, Kathleen A. Farley, Seungil Han, John D. Knafels and Katherine L. Lee,

引用次数: 0

Abstract

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.

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回顾过去：IRAK4 抑制剂 Zimlovisertib (PF-06650833) 结构-活性关系的根本原因分析

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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.