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：

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发现3-（4-（2-（（（1 H-吲哚-5-基）氨基）-5-氟嘧啶-4-基）-1 H-吡唑-1-基）丙腈衍生物作为TYK2选择性抑制剂炎症性肠病的治疗

TYK2介导在免疫介导的疾病中至关重要的IL-23，IL-12和I型IFN驱动的应答的信号传导。在这里，我们报告3-（4-（2-（（（1 H-吲哚-5-基）氨基）-5-氟嘧啶-4-基）-1 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，IC ₅₀值为9 nM，相对于其他三种同源JAK激酶表现出令人满意的选择性特征，并且在淋巴细胞系和人全血上的JAK / STAT信号传导途径中表现出良好的功能效力。在肝微粒体测定研究中，清除率和半衰期为14l分别为11.4 mL / min / g和121.6 min。此外，在硫酸葡聚糖钠结肠炎模型中，14l减少了促炎细胞因子IL-6和TNF-α的产生，并改善了粘膜浸润，增厚和水肿的炎症症状。两者合计，14l是一种选择性的TYK2抑制剂，可用于治疗免疫疾病，值得进一步研究。