Further exploration of the structure-activity relationship of imidazoquinolines; identification of potent C7-substituted imidazoquinolines

Jordan R. Hunt, Peter A. Kleindl, K. Ryan Moulder, Thomas E. Prisinzano, M. Laird Forrest

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Small molecule agonists of TLR7/8, such as imidazoquinolines, are validated agonists for the treatment of cancer and for use in vaccine adjuvants. Imidazoquinolines have been extensively modified to understand the structure-activity relationship (SAR) at the N1- and C2-positions resulting in the clinical drug imiquimod, resiquimod, and several other highly potent analogues. However, the SAR of the aryl ring has not been fully elucidated in the literature. This initial study examines the SAR of C7-substituted imidazoquinolines. These compounds not only demonstrated that TLR7/8 tolerate changes at the C7-position but can increase potency and change their cytokine profiles. The most notable TLR7/8 agonists developed from this study 5, 8, and 14 which are up to 4-fold and 2-fold more active than resiquimod for TLR8 and/or TLR7, respectively, and up to 100-fold more active than the FDA approved imiquimod for TLR7.

Original languageEnglish
Article number126788
JournalBioorganic and Medicinal Chemistry Letters
Volume30
Issue number2
DOIs
StatePublished - Jan 15 2020

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Ltd

Keywords

  • Adjuvants
  • Imidazoquinolines
  • Toll-like Receptor 7
  • Toll-like Receptor 8

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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