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

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    Issue Date
    2012-09-27
    Author
    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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    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.
    URI
    http://hdl.handle.net/1808/23598
    DOI
    https://doi.org/10.1021/jm301066h
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    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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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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