A series of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chemistry. Among them, 4-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-morpholinophenyl)-2-(thiazol-2-yl)but-3-yn-2-ol (12f) was identified as a highly potent NIK inhibitor, along with satisfactory selectivity. The pharmacokinetics of 12f and its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compound 1 developed by Amgen. Oral administration of different doses of 12f in an imiquimod-induced psoriasis mouse model showed effective alleviation of psoriasis, including invasive erythema, swelling, skin thickening, and scales. The underlying pathological mechanism involved attenuation of proinflammatory cytokine and chemokine gene expression, and the infiltration of macrophages after the treatment of 12f. This work provides a foundation for the development of NIK inhibitors, highlighting the potential of developing NIK inhibitors as a new strategy for the treatment of psoriasis.

中文翻译：

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鉴定N-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺衍生物为新型，有力和选择性的NF-κB诱导激酶（NIK）抑制剂，用于治疗牛皮癣。

通过基于结构的药物设计和合成化学方法，获得了一系列具有NF-κB诱导激酶（NIK）抑制活性的N-苯基-7 H-吡咯并[2,3 - d ]嘧啶-4-胺衍生物。其中，4-（3-（（7 H-吡咯并[2,3 - d ]嘧啶-4-基）氨基）-4-吗啉代苯基）-2-（噻唑-2-基）but-3-yn- 2-ol（12f）被认为是一种高效的NIK抑制剂，具有令人满意的选择性。12f的药代动力学及其抑制BEAS-2B细胞中白介素6分泌的能力优于Amgen开发的化合物1。口服不同剂量的12f在咪喹莫特诱发的牛皮癣中，小鼠模型显示出牛皮癣的有效缓解，包括侵入性红斑，肿胀，皮肤增厚和鳞屑。潜在的病理机制涉及促炎性细胞因子和趋化因子基因表达的减弱，以及12f治疗后巨噬细胞的浸润。这项工作为开发NIK抑制剂提供了基础，强调了开发NIK抑制剂作为治疗牛皮癣的新策略的潜力。