鉴定选择性咪唑吡啶 CSF1R 抑制剂

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-04-30 DOI:10.1021/acsmedchemlett.4c00110

John L. Kane Jr.*, Gary Asmussen, Joseph Batchelor, Mandy Cromwell, Malika Fezoui, Maria Fitzgerald, Barret Giese, Tatiana Gladysheva, Stephanie Holley, Kelly Keefe, Michael Kothe, Becky Lam, Sungtaek Lim, Jinyu Liu, Liang Ma, Markus Metz, Andrew A. Scholte, Patrick Shum, LinLi Wei, Lisa Woodworth and Andrea Edling,

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引用次数: 0

摘要

集落刺激因子-1 受体（CSF1R 或 c-FMS）是一种表达在单核吞噬细胞系统（MPS）成员上的 III 类受体酪氨酸激酶，在巨噬细胞、小胶质细胞和相关细胞的正常功能中发挥着关键作用。通过 CSF1R 发出的异常信号与多种疾病状态有关，包括癌症、炎症和神经变性。在这封信中，我们详细介绍了我们为开发新型 CSF1R 抑制剂所做的努力。借鉴以前描述过的化合物，包括 GW2580 (4)，我们发现了一系列基于咪唑并[4,5-b]吡啶支架的新型化合物。最初的结构-活性关系研究最终确定了 36，这是一种具有强效 CSF1R 生化和细胞活性、可接受的体外 ADME 特性以及大鼠口服暴露的先导化合物。

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Identification of Selective Imidazopyridine CSF1R Inhibitors

Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure–activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat.

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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.