Further Exploration of the SAR of Imidazoquinolines; Identification of Potent C7 Substituted Imidazoquinolines
Hunt, J.; Kleindl, P. A.; Moulder, R.; Prisinzano, T. E.; Forrest, M. L.
Show 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.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology and Target Identification of Thio-wurtzine, a Potent Inhibitor of the Opioid Receptors and the Voltage-Dependent Calcium Channels 96%
- Optimization of 3-Cyano-7-cyclopropylamino-pyrazolopyrimidines Toward the Development of an In Vivo Chemical Probe for CSNK2 94%
- Design, synthesis and pharmacological characterization of the first photoswitchable small-molecule agonist for the Atypical Chemokine Receptor 3 93%
Similar papers in this journal
- Synthesis and Characterization of ULK1/2 Kinase Inhibitors that Inhibit Autophagy and Upregulate Expression of Major Histocompatibility Complex I for the Treatment of Non-Small Cell Lung Cancer 94%
- Repurposing of the RIPK1 selective benzooxazepin-4-one scaffold for the development of a type-III LIMK1/2 inhibitor 93%
- A selective and rapid cell-permeable inhibitor of human caspase-3 93%
Similar papers in this journal
- Stretching the structural envelope of isomeric imatinib analogs that reduce β-amyloid production by modulating both β- and γ-secretase cleavages of APP 92%
- Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region 92%
- Hybrid dynamic pharmacophore models as effective tools to identify novel chemotypes for anti-TB inhibitor design: A case study with Mtb-DapB 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.