Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis
Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis
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鉴定 N-苯基-7H-吡咯并[2,3-d]嘧啶-4-胺衍生物作为治疗银屑病的新型、有效和选择性 NF-κB 诱导激酶 (NIK) 抑制剂
DOI：
10.1021/acs.jmedchem.0c00055
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发表时间：
2020
影响因子：
7.3
通讯作者：
Yadong Chen
中科院分区：
文献类型：
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作者：
Yuqin Zhu;Yuxiang Ma;Weidong Zu;Jianing Song;Hua Wang;You Zhong;Hongmei Li;Yanmin Zhang;Qianqian Gao;Bo Kong;Junyu Xu;Fei Jiang;Xinren Wang;Shuwen Li;Chenhe Liu;Haichun Liu;Tao Lu;Yadong Chen
通过基于结构的药物设计和合成化学方法，合成了一系列具有NF-κB诱导激酶（NIK）抑制活性的N-苯基-7H-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）丁-3-炔-2-醇（12 f）被鉴定为高效的NIK抑制剂，沿着具有令人满意的选择性。12 f的药代动力学和抑制BEAS-2B细胞分泌白细胞介素6的能力优于Amgen开发的化合物1。在咪喹莫特诱导的银屑病小鼠模型中，口服不同剂量的12 fin可有效缓解银屑病，包括侵袭性红斑、肿胀、皮肤增厚和鳞屑。潜在的病理机制涉及12 f处理后促炎细胞因子和趋化因子基因表达的减弱以及巨噬细胞的浸润。这项工作为NIK抑制剂的开发提供了基础，突出了开发NIK抑制剂作为治疗银屑病的新策略的潜力。
A series ofN-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 of12fand its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compound1developed by Amgen. Oral administration of different doses of12fin 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 of12f. 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.