Structure-Activity Relationship in Human Toll-like Receptor 2- Specific Monoacyl Lipopeptides

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Issue Date
2010-06-10Author
Shukla, Nikunj M.
Malladi, Subbalakshmi S.
Mutz, Cole A.
Balakrishna, Rajalakshmi
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/jm900254k.
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Show full item recordAbstract
Engagement of toll-like receptors serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. A structure-activity study was conducted on the TLR7-agonistic imidazoquinolines, starting with 1-(4-amino-2-((ethylamino)methyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a lead. Modifications of the secondary amine of the C2 ethylaminomethylene sidechain are poorly tolerated. The 4-amino group must be retained for activity. Replacement of the imidazole ring of the scaffold with triazole or cyclic urea led to complete loss of activity. A systematic exploration of N1-benzyl-C2-alkyl substituents showed a very distinct relationship between alkyl length and TLR7-agonistic potency with the optimal compound bearing a C2-n-butyl group. Transposition of the N1 and C2 substituents led to the identification of an extremely active TLR7-agonistic compound with an EC50 value of 8.6 nM. The relative potencies in human TLR7-based primary reporter gene assays were paralleled by interferon-α induction activities in whole human blood models.
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Citation
Shukla, N. M., Malladi, S. S., Mutz, C. A., Balakrishna, R., & David, S. A. (2010). Structure-Activity Relationships in Human Toll-like Receptor 7-Active Imidazoquinoline Analogues. Journal of Medicinal Chemistry, 53(11), 4450–4465. http://doi.org/10.1021/jm100358c
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