RESUMO
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.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Interferons/agonistas , Receptor 7 Toll-Like/agonistas , Aldeído Oxidase/metabolismo , Animais , Antivirais/química , Antivirais/farmacocinética , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Hepacivirus/fisiologia , Hepatite C/virologia , Humanos , Injeções Intravenosas , Indutores de Interferon/síntese química , Indutores de Interferon/química , Indutores de Interferon/farmacocinética , Indutores de Interferon/farmacologia , Microssomos Hepáticos/metabolismo , Terapia de Alvo Molecular , Peso Molecular , Purinas/síntese química , Purinas/metabolismo , Ratos , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antivirais/química , Hepacivirus/efeitos dos fármacos , Purinas/química , Infecções por Vírus de RNA/tratamento farmacológico , Receptor 7 Toll-Like/agonistas , Administração Oral , Animais , Antivirais/síntese química , Antivirais/uso terapêutico , Desenho de Fármacos , Camundongos , Modelos Animais , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismoRESUMO
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.