Structure-Activity Relationships in Human Toll-like Receptor 8-Active 2,3-diamino-furo[2,3-c]pyridines

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Issue Date
2012-09-27Author
Salunke, Deepak B.
Yoo, Euna
Shukla, Nikunj M.
Balakrishna, Rajalakshmi
Malladi, Subbalakshmi S.
Serafin, Katelyn J.
Day, Victor W.
Wang, Xinkun
David, Sunil A.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm301066h.
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Show full item recordAbstract
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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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
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