RESUMO
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.
Assuntos
Glicoproteínas de Membrana/agonistas , Quinazolinas/farmacologia , Receptor 7 Toll-Like/agonistas , Animais , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Células HEK293 , Meia-Vida , Humanos , Interferon-alfa/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Receptor 8 Toll-Like/agonistasRESUMO
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.
Assuntos
Antivirais/síntese química , Hepatite B/tratamento farmacológico , Pirimidinas/síntese química , Pirróis/síntese química , Receptor 7 Toll-Like/agonistas , Administração Oral , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Cães , Feminino , Genes Reporter , Células HEK293 , Hepatite B/imunologia , Humanos , Imunoterapia , Interferons/biossíntese , Macaca fascicularis , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade , Receptor 7 Toll-Like/genética , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/genéticaRESUMO
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.
Assuntos
Antiparasitários/síntese química , Colestadienóis/síntese química , Euphorbia/química , Lanosterol/análogos & derivados , Extratos Vegetais/síntese química , Animais , Antiparasitários/química , Antiparasitários/farmacologia , Células CHO , Colestadienóis/química , Colestadienóis/farmacologia , Cricetinae , Cricetulus , Lanosterol/síntese química , Lanosterol/química , Lanosterol/farmacologia , Leishmania infantum/efeitos dos fármacos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Trypanosoma cruzi/efeitos dos fármacosRESUMO
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.