Discovery of Novel Azaindoles as Potent and Selective PI3Kδ Inhibitors for Treatment of Multiple Sclerosis,Journal of Medicinal Chemistry

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Discovery of Novel Azaindoles as Potent and Selective PI3Kδ Inhibitors for Treatment of Multiple Sclerosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-05-16 , DOI: 10.1021/acs.jmedchem.4c00788
Mengyao Yu ₁ , Xian Wang ₁ , Yongmei Tang ₁ , Longling Wang ₁ , Xueping Hu ₂ , Qinjie Weng _{1,

3} , Jiajia Wang ₁ , Sunliang Cui ₁

Affiliation

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system and the unmet need for MS treatment demands new therapeutic development. Particularly, PI3Kδ is a high-value target for autoimmune disease, while the investigation of PI3Kδ inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3Kδ inhibitors for MS treatment. Compound 31, designed via nitrogen bioisosterism, displayed excellent PI3Kδ inhibitory activity and selectivity. In vitro assay showed that 31 exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4⁺, CD8⁺, and CD3⁺ T cells. In the experimental autoimmune encephalomyelitis (EAE) model, 31 showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound 31 could significantly inhibit the PI3K/AKT/mTOR signaling pathway and inhibited T-cell proliferation and differentiation. Overall, this work provides a new structural PI3Kδ inhibitor and a new vision for MS therapy.

中文翻译：

发现新型氮杂吲哚作为治疗多发性硬化症的有效和选择性 PI3Kδ 抑制剂

多发性硬化症 (MS) 是一种中枢神经系统慢性自身免疫性疾病，多发性硬化症治疗的未满足需求需要新的治疗方法的开发。特别是，PI3Kδ是自身免疫性疾病的高价值靶点，而PI3Kδ抑制剂用于多发性硬化症治疗的研究相对较少。在此，我们报告了一类新型氮杂吲哚作为 PI3Kδ 抑制剂用于 MS 治疗。通过氮生物等排作用设计的化合物31表现出优异的PI3Kδ抑制活性和选择性。体外试验表明， 31对 T 淋巴细胞表现出优异的活性，可抑制 CD4 ⁺ 、CD8 ⁺和 CD3 ⁺ T 细胞的增殖。在实验性自身免疫性脑脊髓炎 (EAE) 模型中， 31表现出与地塞米松相当的治疗效果，可显着改善 EAE 症状。机理研究表明，化合物31能够显着抑制PI3K/AKT/mTOR信号通路，抑制T细胞增殖和分化。总体而言，这项工作提供了一种新的结构 PI3Kδ 抑制剂，并为 MS 治疗提供了新的愿景。

更新日期：2024-05-16

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