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

Author

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  • Snehil Singh
  • Sagar Patni
  • Ajay Kumar
  • Amrita Singh
  • Shashi Kiran Misra

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.

Suggested Citation

  • Snehil Singh & Sagar Patni & Ajay Kumar & Amrita Singh & Shashi Kiran Misra, 2026. "Design, Synthesis, And Biological Evolution of Aryl-Substituted [1,2,4] Triazolo[1,5-A] Pyridine Analogues as Potential Selective JAK1 Inhibitors," International Journal of Scientific Research in Chemistry, International Journal of Scientific Research in Chemistry, vol. 11(5), pages 41-51, September.
    • Handle: RePEc:cuo:ijsrch:v11:y2026:i5:id:110
    DOI: 10.32628/IJSRCH261155
    Note: Article URL: https://ijsrch.com/home/article/view/IJSRCH261155
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