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.,Journal of Medicinal Chemistry

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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.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-01 , DOI: 10.1021/acs.jmedchem.0c00055
Yuqin Zhu ₁ , Yuxiang Ma ₂ , Weidong Zu ₁ , Jianing Song ₁ , Hua Wang ₂ , You Zhong ₂ , Hongmei Li ₁ , Yanmin Zhang ₁ , Qianqian Gao ₁ , Bo Kong ₁ , Junyu Xu ₁ , Fei Jiang ₁ , Xinren Wang ₁ , Shuwen Li ₁ , Chenhe Liu ₁ , Haichun Liu ₁ , Tao Lu _{1,

2} , Yadong Chen ₁

Affiliation

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：

鉴定 N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 衍生物作为治疗银屑病的新型、有效、选择性 NF-κB 诱导激酶 (NIK) 抑制剂。

通过基于结构的药物设计和合成化学，获得了一系列具有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-yn- 2-ol ( 12f ) 被认为是一种高效的 NIK 抑制剂，并且具有令人满意的选择性。 12f的药代动力学及其抑制BEAS-2B细胞中白细胞介素6分泌的能力优于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12f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促炎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NIK抑制剂的开发奠定了基础，凸显了开发NIK抑制剂作为治疗银屑病新策略的潜力。

更新日期：2020-07-09

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