What does this research mean for the field?

Compound 38 is a gut-restricted selective JAK1 inhibitor that significantly ameliorates inflammatory symptoms in a DSS-induced colitis model, making it a promising candidate for treating inflammatory bowel disease. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The aim is to develop selective JAK1 inhibitors that minimize systemic side effects for treating inflammatory bowel disease.

February 26, 2026Journal of Medicinal Chemistry1 citations

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

HYHao YueShenyang Pharmaceutical University YBYu BaoShenyang Pharmaceutical University JXJialong XingShenyang Pharmaceutical University

Key Points

The aim is to develop selective JAK1 inhibitors that minimize systemic side effects for treating inflammatory bowel disease.
Designed and synthesized 2,4-diaminopyrimidine derivatives as JAK1 inhibitors.
Evaluated potency in vitro using JAK/STAT signaling pathway assays.
Analyzed intestinal vs. systemic exposure in mice using pharmacokinetic studies.
Examined efficacy in a DSS-induced colitis model.
Compound 38 showed potent JAK1 inhibition with IC50 < 0.5 nM.
Demonstrated robust cellular potency (IC50 = 28 nM) and high selectivity over JAK2, JAK3, and TYK2.
Exhibited high intestinal exposure and low systemic exposure (<1 ng/mL).
Significantly reduced inflammatory symptoms and promoted epithelial repair in the colitis model.

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

Key Points

Abstract

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