Structure-activity relationships in human toll-like receptor 7-active imidazoquinoline analogues

Nikunj M. Shukla, Subbalakshmi S. Malladi, Cole A. Mutz, Rajalakshmi Balakrishna, Sunil A. David

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


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 side chain 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 N 1 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.

Original languageEnglish (US)
Pages (from-to)4450-4465
Number of pages16
JournalJournal of medicinal chemistry
Issue number11
StatePublished - Jun 10 2010


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