Identification of 2,4-Diaminopyrimidine Derivatives as Novel Gut-Restricted Selective JAK1 Inhibitors for the Treatment of Inflammatory Bowel Disease

Journal of Medicinal Chemistry 2026

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Authors: Hao Yue, Yu Bao, Jialong Xing, Yuxuan Wang, Na Zhang, Tingjun Wang, Donghao Jia, Chang Li, Liang Han, Ya Wang, Xuan Shi, Minghui Tong
+2 more Yunlei Hou, Yanfang Zhao
DOI: 10.1021/acs.jmedchem.5c03563
Cited by: 1
References: 36

Abstract

JAK1 represents a clinically validated target for inflammatory bowel disease (IBD), but the safety concerns associated with systemic JAK1 inhibition remain unaddressed. In this study, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as novel, gut-restricted, selective JAK1 inhibitors for the treatment of IBD to mitigate potential systemic side effects. Among them, compound 38 exhibited potent JAK1 inhibition (IC 50 < 0.5 nM) and robust cellular potency (IC 50 = 28 nM) in the JAK/STAT signaling pathway. It also demonstrated remarkable selectivity over JAK2 (>312-fold), JAK3 (>20,000-fold), and TYK2 (>354-fold), respectively. Furthermore, compound 38 displayed high intestinal exposure but low systemic exposure (

Fields of Study & Subjects

Cytokine Signaling Pathways and Interactions Myeloproliferative Neoplasms: Diagnosis and Treatment Inflammatory Bowel Disease

Publication details

Journal / source
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Volume
69
Issue
5
Pages
6084–6110
Publication date
24 February 2026
Language
EN