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
posted on 2020-06-16, 15:37authored byYuqin 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
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.