RESUMEN
The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Interferones/agonistas , Receptor Toll-Like 7/agonistas , Aldehído Oxidasa/metabolismo , Animales , Antivirales/química , Antivirales/farmacocinética , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Hepacivirus/fisiología , Hepatitis C/virología , Humanos , Inyecciones Intravenosas , Inductores de Interferón/síntesis química , Inductores de Interferón/química , Inductores de Interferón/farmacocinética , Inductores de Interferón/farmacología , Microsomas Hepáticos/metabolismo , Terapia Molecular Dirigida , Peso Molecular , Purinas/síntesis química , Purinas/metabolismo , Ratas , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
Asunto(s)
Antivirales/química , Hepacivirus/efectos de los fármacos , Purinas/química , Infecciones por Virus ARN/tratamiento farmacológico , Receptor Toll-Like 7/agonistas , Administración Oral , Animales , Antivirales/síntesis química , Antivirales/uso terapéutico , Diseño de Fármacos , Ratones , Modelos Animales , Purinas/farmacocinética , Purinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Receptor Toll-Like 7/metabolismoRESUMEN
The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.
