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

  • J Med Chem. 2026 Mar 12;69(5):6084-6110. doi: 10.1021/acs.jmedchem.5c03563.
Hao Yue  1 ,  Yu Bao  2 ,  Jialong Xing  1 ,  Yu Wang  1 ,  Na Zhang  1 ,  Tingjun Wang  1 ,  Donghao Jia  1 ,  Chunting Li  1 ,  Liang Han  3 ,  Zhaohui Wang  3 ,  Xuan Shi  3 ,  Minghui Tong  3 ,  Yunlei Hou  1 ,  Yanfang Zhao  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. School of Clinical Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
  • 3. SunShine Innovation Co., Ltd, Xiamen Torch Hi-Tech Industrial Zone Software Park Phase III Unit 209-0887, No. 62 Chengyi North Street, Xiamen 361021, PR China.
PMID: 41735285 DOI: 10.1021/acs.jmedchem.5c03563
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 (IC50 < 0.5 nM) and robust cellular potency (IC50 = 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 (<1 ng/mL) in mice, confirming its gut-restricted nature. In a DSS-induced colitis model, compound 38 significantly ameliorated inflammatory symptoms, promoted epithelial repair, and suppressed the production of proinflammatory cytokines (e.g., TNF-α and IL-6). Thus, compound 38 was identified as a therapeutically promising candidate compound for treating IBD.

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