RESUMEN
In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure-activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.
Asunto(s)
Pirimidinas/farmacología , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Administración Oral , Animales , Diseño de Fármacos , Ratones , Relación Estructura-ActividadRESUMEN
A novel series of 2,4-diaminoquinazolines was identified as potent dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target activity. The stereochemistry of the amino alcohol was found to influence the TLR7/8 selectivity with the ( R) isomer resulting in selective TLR8 agonism. Lead optimization toward a dual agonist afforded ( S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol 31 as a potent analog, being structurally different from previously described dual agonists ( McGowan J. Med. Chem. 2016 , 59 , 7936 ). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the desired high first pass profile aimed at limiting systemic cytokine activation. In vivo pharmacodynamic studies with lead compound 31 demonstrated production of cytokines consistent with TLR7/8 activation in mice and cynomolgus monkeys and ex vivo inhibition of hepatitis B virus (HBV).
Asunto(s)
Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Quinazolinas/farmacología , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , Animales , Antivirales/química , Antivirales/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Conformación Proteica , Quinazolinas/química , Quinazolinas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Receptor Toll-Like 7/química , Receptor Toll-Like 8/químicaRESUMEN
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.
