biostudies-literatureDeYoung EGNational Institute of Allergy and Infectious DiseasesNIAID NIH HHSNCI NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHSHeidelberg Pharma AG1358-1368https://www.ebi.ac.uk/biostudies/studies/S-EPMC10577892biostudies-literatureUnknown14(10)TLR7 agonists have significant therapeutic potential in a variety of oncology and autoimmune applications. We recently reported a potent TLR7 selective agonist <b>1</b> that could be delivered by antibody-drug conjugate (ADC) technology to elicit potent anticancer activity. Herein we report synthetic chemistry and structure-activity relationship studies to develop TLR7 agonists with improved potency for next-generation ADC efforts. We found that the addition of hydrophobic acyl tails to parent compound <b>1</b> generally resulted in retained or improved TLR7 agonist activity without sacrificing the permeability or the selectivity over TLR8. In contrast, the addition of a simple alkyl tail at the same position resulted in a dramatic loss in potency. Molecular modeling was performed to proviACS medicinal chemistry lettersSynthesis and Optimization of 1-Substituted Imidazo[4,5-<i>c</i>]quinoline TLR7 Agonists.PMC10577892R01GM140026R01 GM140026R15 AI149755R15 CA2277471R15AI149755-01Tumey LNHandel JPGillen Miller JTDeYoung EGReddy MMFang SHowe JMWheeler DRfalseSynthesis and Optimization of 1-Substituted Imidazo[4,5-<i>c</i>]quinoline TLR7 Agonists.TLR7 agonists have significant therapeutic potential in a variety of oncology and autoimmune applications. We recently reported a potent TLR7 selective agonist <b>1</b> that could be delivered by antibody-drug conjugate (ADC) technology to elicit potent anticancer activity. Herein we report synthetic chemistry and structure-activity relationship studies to develop TLR7 agonists with improved potency for next-generation ADC efforts. We found that the addition of hydrophobic acyl tails to parent compound <b>1</b> generally resulted in retained or improved TLR7 agonist activity without sacrificing the permeability or the selectivity over TLR8. In contrast, the addition of a simple alkyl tail at the same position resulted in a dramatic loss in potency. Molecular modeling was performed to provi2023-01-01T00:00:00Z2023 Oct2026-06-03T03:48:16.091Z2025-04-06T13:21:03.977ZS-EPMC105778923784953010.1021/acsmedchemlett.3c00260