ABSTRACT
The discovery of a novel series of highly potent quinazoline TLR 7/8 agonists is described. The synthesis and structure-activity relationship is presented. Structural requirements and optimization of this series toward TLR 7 selectivity afforded the potent agonist 48. Pharmacokinetic and pharmacodynamic studies highlighted 48 as an orally available endogenous interferon (IFN-α) inducer in mice.
Subject(s)
Membrane Glycoproteins/agonists , Quinazolines/pharmacology , Toll-Like Receptor 7/agonists , Animals , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors/pharmacology , HEK293 Cells , Half-Life , Humans , Interferon-alpha/metabolism , Male , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Quinazolines/chemical synthesis , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship , Toll-Like Receptor 8/agonistsABSTRACT
Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.
Subject(s)
Antiviral Agents/chemical synthesis , Hepatitis B/drug therapy , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Toll-Like Receptor 7/agonists , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Dogs , Female , Genes, Reporter , HEK293 Cells , Hepatitis B/immunology , Humans , Immunotherapy , Interferons/biosynthesis , Macaca fascicularis , Madin Darby Canine Kidney Cells , Mice, Inbred C57BL , Molecular Docking Simulation , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Structure-Activity Relationship , Toll-Like Receptor 7/genetics , Toll-Like Receptor 8/agonists , Toll-Like Receptor 8/geneticsABSTRACT
Fifteen semisynthetic terpenoid derivatives from the major latex components of Euphorbia officinarum have been evaluated against the insect pest Spodoptera littoralis, two species of protozoan parasites, Trypanosoma cruzi and Leishmania infantum, and also against insect Sf9 and mammalian CHO cells to test their selective cytotoxicity. Our results showed that 40% of the test substances were postingestive toxicants to S. littoralis. All the tested derivatives had cytotoxic effects on insect-derived Sf9 cells, whereas mammalian CHO cells were affected by a lower number of compounds (47%). Furthermore, 87% of the test compounds had antiparasitic effects on both L. infantum and T. cruzi, with some of them being selective parasite toxicants.
Subject(s)
Antiparasitic Agents/chemical synthesis , Cholestadienols/chemical synthesis , Euphorbia/chemistry , Lanosterol/analogs & derivatives , Plant Extracts/chemical synthesis , Animals , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , CHO Cells , Cholestadienols/chemistry , Cholestadienols/pharmacology , Cricetinae , Cricetulus , Lanosterol/chemical synthesis , Lanosterol/chemistry , Lanosterol/pharmacology , Leishmania infantum/drug effects , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/pharmacology , Trypanosoma cruzi/drug effectsABSTRACT
Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.
