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Further exploration of the structure-activity relationship of imidazoquinolines; identification of potent C7-substituted imidazoquinolines.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Jan 15; Vol. 30 (2), pp. 126788. Date of Electronic Publication: 2019 Nov 09. - Publication Year :
- 2020
-
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.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Binding Sites
Cytokines metabolism
Humans
Imidazoles chemistry
Leukocytes, Mononuclear cytology
Leukocytes, Mononuclear drug effects
Leukocytes, Mononuclear metabolism
Molecular Docking Simulation
Quinolines metabolism
Structure-Activity Relationship
Toll-Like Receptor 7 metabolism
Toll-Like Receptor 8 metabolism
Quinolines chemistry
Toll-Like Receptor 7 agonists
Toll-Like Receptor 8 agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 30
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 31784317
- Full Text :
- https://doi.org/10.1016/j.bmcl.2019.126788