Structure-activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines

Euna Yoo, Breanna M. Crall, Rajalakshmi Balakrishna, Subbalakshmi S. Malladi, Lauren M. Fox, Alec R. Hermanson, Sunil A. David

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34 Scopus citations


Engagement of TLR7 in plasmacytoid dendritic cells leads to the induction of IFN-α/β which plays essential functions in the control of adaptive immunity. We had previously examined structure-activity relationships (SAR) in TLR7/8-agonistic imidazoquinolines with a focus on substituents at the N 1, C2, N3 and N4 positions, and we now report SAR on 1H-imidazo[4,5-c]pyridines. 1-Benzyl-2-butyl-1H-imidazo[4,5-c] pyridin-4-amine was found to be a pure TLR7-agonist with negligible activity on TLR8. Increase in potency was observed in N6-substituted analogues, especially in those compounds with electron-rich substituents. Direct aryl-aryl connections at C6 abrogated activity, but TLR7 agonism was reinstated in 6-benzyl and 6-phenethyl analogues. Consistent with the pure TLR7-agonistic behavior, prominent IFN-α induction in human PBMCs was observed with minimal proinflammatory cytokine induction. A benzologue of imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine. Distinct differences in N6-substituted analogues were observed with respect to IFN-α induction in human PBMCs on the one hand, and CD69 upregulation in lymphocytic subsets, on the other.

Original languageEnglish (US)
Pages (from-to)6526-6545
Number of pages20
JournalOrganic and Biomolecular Chemistry
Issue number38
StatePublished - Oct 14 2013


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