Design, Synthesis, And Biological Evolution of Aryl-Substituted [1,2,4] Triazolo[1,5-A] Pyridine Analogues as Potential Selective JAK1 Inhibitors

Snehil Singh, Sagar Patni, Ajay Kumar, Amrita Singh and Shashi Kiran Misra

International Journal of Scientific Research in Chemistry, 2026, vol. 11, issue 5, 41-51

Abstract: JAK1 is a validated target for autoimmune/inflammatory diseases via central cytokine JAK-STAT signaling. Based on the filgotinib scaffold, a series of ortho- and meta-substituted triazolo[1,5-a]pyridine derivatives was rationally designed to improve JAK1 potency/selectivity. Structure-based docking guided optimization of hinge H-bonding and hydrophobic occupancy in the ATP pocket, with SAR showing critical substituent position effects and meta-analogues superior. SS_INT_5h emerged as lead with potent JAK1 inhibition (IC₅₀ = 24 nM), effective JAK/STAT suppression in cells and minimal cytotoxicity (95% viability), validating triazolo[1,5-a]pyridine as a promising platform for selective JAK1 inhibitors.

Keywords: JAK (Janus kinase) inhibitor; Cytokines; Immune-mediated diseases; JAK-STAT pathway; Scaffold optimization; Filgotinib (search for similar items in EconPapers)
Date: 2026
Note: Article URL: https://ijsrch.com/home/article/view/IJSRCH261155
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Persistent link: https://EconPapers.repec.org/RePEc:cuo:ijsrch:v11:y2026:i5:id:110

DOI: 10.32628/IJSRCH261155

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