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Issue 38, 2013
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Structure–activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines

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Abstract

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 N1, 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.

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

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Article information


Submitted
22 Apr 2013
Accepted
15 Aug 2013
First published
15 Aug 2013

This article is Open Access

Org. Biomol. Chem., 2013,11, 6526-6545
Article type
Paper

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

E. Yoo, B. M. Crall, R. Balakrishna, S. S. Malladi, L. M. Fox, A. R. Hermanson and S. A. David, Org. Biomol. Chem., 2013, 11, 6526
DOI: 10.1039/C3OB40816G

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