Structure-activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines
| Autor: | Breanna M. Crall, Subbalakshmi S. Malladi, Lauren M. Fox, Alec R. Hermanson, Euna Yoo, Rajalakshmi Balakrishna, Sunil A. David |
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| Rok vydání: | 2013 |
| Předmět: |
Immunoassay
Toll-like receptor Imidazopyridine Chemistry Stereochemistry Pyridines Organic Chemistry Imidazoles Interferon-alpha TLR7 TLR8 Pharmacology Acquired immune system Biochemistry Proinflammatory cytokine Imidazoquinoline chemistry.chemical_compound Structure-Activity Relationship HEK293 Cells Downregulation and upregulation Toll-Like Receptor 7 Leukocytes Mononuclear Cytokines Humans Physical and Theoretical Chemistry |
| Zdroj: | Organicbiomolecular chemistry. 11(38) |
| ISSN: | 1477-0539 |
| Popis: | 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), C(2), N(3) and N(4) 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 N(6)-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 N(6)-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. |
| Databáze: | OpenAIRE |
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