Discovery of 3-(4-(2-((1H-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease,Journal of Medicinal Chemistry

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Discovery of 3-(4-(2-((1H-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-02-16 , DOI: 10.1021/acs.jmedchem.0c01468
Chufeng Zhang ₁ , Wenyan Qi ₁ , Yong Li ₁ , Minghai Tang ₁ , Tao Yang ₁ , Kongjun Liu ₁ , Yong Chen ₁ , Dexin Deng ₁ , Mingli Xiang ₁ , Lijuan Chen ₁

Affiliation

TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure–activity relationships (SARs) of 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound 14l exhibited acceptable TYK2 inhibition with an IC₅₀ value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of 14l were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, 14l reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, 14l was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.

中文翻译：

发现 3-(4-(2-((1H-吲哚-5-基)氨基)-5-氟嘧啶-4-基)-1H-吡唑-1-基)丙腈衍生物作为选择性 TYK2 抑制剂用于治疗炎症性肠病

TYK2 介导 IL-23、IL-12 和 I 型 IFN 驱动反应的信号传导，这些反应对于免疫介导的疾病至关重要。在此，我们报告了 3-(4-(2-((1 H -indol-5-yl)amino)-5-氟嘧啶-4-yl)-1 的设计、合成和构效关系 (SAR) H-吡唑-1-基)丙腈衍生物作为选择性 TYK2 抑制剂。其中，化合物14l表现出可接受的TYK2抑制作用，IC ₅₀值为9 nM，与其他三种同源JAK激酶相比表现出令人满意的选择性特性，并且在淋巴细胞系和人全血的JAK/STAT信号通路中表现出良好的功能效力。在肝微粒体测定研究中， 14l的清除率和半衰期分别为11.4 mL/min/g和121.6 min。此外，在葡聚糖硫酸钠结肠炎模型中， 14l减少了促炎细胞因子IL-6和TNF-α的产生，改善了粘膜浸润、增厚和水肿的炎症症状。综上所述， 14l是一种选择性TYK2抑制剂，可用于治疗免疫性疾病，值得进一步研究。

更新日期：2021-02-25

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