RESUMEN
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.
Asunto(s)
Glicoproteínas de Membrana/agonistas , Quinazolinas/farmacología , Receptor Toll-Like 7/agonistas , Animales , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Inhibidores Enzimáticos del Citocromo P-450/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Células HEK293 , Semivida , Humanos , Interferón-alfa/metabolismo , Masculino , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Receptor Toll-Like 8/agonistasRESUMEN
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.
Asunto(s)
Antivirales/síntesis química , Hepatitis B/tratamiento farmacológico , Pirimidinas/síntesis química , Pirroles/síntesis química , Receptor Toll-Like 7/agonistas , Administración Oral , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Perros , Femenino , Genes Reporteros , Células HEK293 , Hepatitis B/inmunología , Humanos , Inmunoterapia , Interferones/biosíntesis , Macaca fascicularis , Células de Riñón Canino Madin Darby , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Relación Estructura-Actividad , Receptor Toll-Like 7/genética , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/genéticaRESUMEN
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.
Asunto(s)
Antivirales/química , Virus de la Hepatitis B/efectos de los fármacos , Pirimidinas/química , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Antivirales/farmacología , Simulación por Computador , Citocinas/biosíntesis , Perros , Hepatitis B/tratamiento farmacológico , Hepatitis B/virología , Virus de la Hepatitis B/fisiología , Ensayos Analíticos de Alto Rendimiento , Humanos , Macaca fascicularis , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
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.