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Structure-Activity Relationships in Human Toll-like Receptor 8-Active 2,3-diamino-furo[2,3-c]pyridines
Salunke, Deepak B. Yoo, Euna Shukla, Nikunj M. Balakrishna, Rajalakshmi Malladi, Subbalakshmi S. Serafin, Katelyn J. Day, Victor W. Wang, Xinkun David, Sunil A.
Salunke, Deepak B.
Yoo, Euna
Shukla, Nikunj M.
Balakrishna, Rajalakshmi
Malladi, Subbalakshmi S.
Serafin, Katelyn J.
Day, Victor W.
Wang, Xinkun
David, Sunil A.
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Abstract
In our ongoing search toward identifying novel and synthetically simpler candidate vaccine adjuvants, we hypothesized that the imidazo[1,2-a]pyrazines, readily accessible via the Groebke-Blackburn-Bienaymé multicomponent reaction, would possess sufficient structural similarity with TLR7/8-agonistic imidazoquinolines. With pyridoxal as the aldehyde component, furo[2,3- c]pyridines, rather than the expected imidazo[1,2-a]pyridines were obtained, which were characterized by NMR spectroscopy and crystallography. Several analogues were found to activate TLR8-dependent NF-κB signaling. In a focused library of furo[2,3-c]pyridines, a distinct SAR was observed with varying substituents at C2. In human PBMCs, none of the furo[2,3-c]pyridines showed any proinflammatory cytokine induction, but upregulated several chemokine ligand genes. In immunization studies in rabbits, the most active compound showed prominent adjuvantic effects. The complete lack of proinflammatory cytokine induction coupled with strong adjuvantic activity of the novel furo[2,3-c]pyridines render this hitherto unknown chemotype an attractive class of compounds which are expected to be devoid of local or systemic reactogenicity.
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Date
2012-09-27
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American Chemical Society
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Keywords
TLR8, TLR8 agonists, Vaccine adjuvants, Innate immunity, Furopyridines
Citation
Salunke, D. B., Yoo, E., Shukla, N. M., Balakrishna, R., Malladi, S. S., Serafin, K. J., … David, S. A. (2012). Structure-Activity Relationships in Human Toll-like Receptor 8-Active 2,3-diamino-furo[2,3-c]pyridines. Journal of Medicinal Chemistry, 55(18), 8137–8151. http://doi.org/10.1021/jm301066h