<br>发现 N-(5-酰胺基-2-甲基苯基)-5-甲基异恶唑-3-甲酰胺作为双重 CSF-1R/c-Kit 抑制剂，具有更高的稳定性和 BBB 通透性,European Journal of Medicinal Chemistry

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发现 N-(5-酰胺基-2-甲基苯基)-5-甲基异恶唑-3-甲酰胺作为双重 CSF-1R/c-Kit 抑制剂，具有更高的稳定性和 BBB 通透性
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-02-20 , DOI: 10.1016/j.ejmech.2024.116253
Jihyun Baek ₁ , Hyejin Kim ₁ , Joonhong Jun ₁ , Dahyun Kang ₁ , Hyunah Bae ₁ , Hyunwook Cho ₁ , Jung-Mi Hah ₁

Affiliation

本研究探讨了 CSF-1R 抑制剂作为神经退行性疾病治疗药物的潜力。 CSF-1R 是一种主要在巨噬细胞谱系中表达的受体酪氨酸激酶，在调节各种细胞过程中发挥着关键作用。最近的研究强调了 CSF-1R 抑制在减轻神经炎症方面的重要性，特别是在阿尔茨海默病中，小胶质细胞过度激活会导致神经退行性变。研究揭示了一系列-(5-酰胺基-2-甲基苯基)-5-甲基异恶唑-3-甲酰胺CSF-1R抑制剂，其中化合物、、和表现出出色的抑制活性和选择性，IC值为33、31和分别为 64 nM。该系列中这些最有前途的化合物进行了细胞效力分析并进行了药代动力学分析。这些抑制剂即使在较高浓度下也表现出最小的细胞毒性，并且具有良好的血脑屏障渗透性，使其成为中枢神经系统疾病的潜在候选者。对 ADME 特性（包括血浆和微粒体稳定性）的研究表明，这些 CSF-1R 抑制剂保持其结构完整性和血浆浓度。这种弹性使它们能够进一步发展为神经退行性疾病的治疗剂。

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Discovery of N-(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide as dual CSF-1R/c-Kit Inhibitors with improved stability and BBB permeability

This study explores the potential of CSF-1R inhibitors as therapeutic agents for neurodegenerative diseases. CSF-1R, a receptor tyrosine kinase primarily expressed in macrophage lineages, plays a pivotal role in regulating various cellular processes. Recent research highlights the significance of CSF-1R inhibition in mitigating neuroinflammation, particularly in Alzheimer's disease, where microglial overactivation contributes to neurodegeneration. The research reveals a series of -(5-amido-2-methylphenyl)-5-methylisoxazole-3-carboxamide CSF-1R inhibitors, where compounds , , and exhibit outstanding inhibitory activities and selectivity, with IC values of 33, 31, and 64 nM, respectively. These most promising compounds in this series were profiled for cellular potency and subjected to pharmacokinetic profiling. These inhibitors exhibit minimal cytotoxicity, even at higher concentrations, and possess promising blood-brain barrier permeability, making them potential candidates for central nervous system diseases. The investigation into the ADME properties, including plasma and microsomal stability, reveals that these CSF-1R inhibitors maintain their structural integrity and plasma concentration. This resilience positions them for further development as therapeutic agents for neurodegenerative diseases.

更新日期：2024-02-20

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