RESUMEN
Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as representing a serious threat to patient groups with poorly functioning or immature immune systems. Racemic 1,4-benzodiazepines show potent anti-RSV activity in vitro. Anti-RSV evaluation of 3-position R- and S-benzodiazepine enantiomers and subsequent optimization of this series resulted in selection of a clinical candidate. Antiviral activity was found to reside mainly in the S-enantiomer, and the R-enantiomers were consistently less active against RSV. Analogues of 1,4-(S)-benzodiazepine were synthesized as part of the lead optimization program at Arrow and tested in the XTT assay. From this exercise, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-urea, 17b (RSV-604) was identified as a clinical candidate, exhibiting potent anti-RSV activity in the XTT assay, which was confirmed in secondary assays. Compound 17b also possessed a good pharmacokinetic profile and has now progressed into the clinic.
Asunto(s)
Antivirales/síntesis química , Benzodiazepinas/síntesis química , Benzodiazepinonas/síntesis química , Compuestos de Fenilurea/síntesis química , Virus Sincitiales Respiratorios/efectos de los fármacos , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Benzodiazepinas/farmacocinética , Benzodiazepinas/farmacología , Benzodiazepinonas/farmacocinética , Benzodiazepinonas/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Ensayo de Inmunoadsorción Enzimática , Humanos , Técnicas In Vitro , Microsomas/metabolismo , Estructura Molecular , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ensayo de Placa ViralRESUMEN
Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as a serious threat to patient groups with poorly functioning immune systems. Our approach to finding a novel inhibitor of this virus was to screen a 20 000-member diverse library in a whole cell XTT assay. Parallel assays were carried out in the absence of virus in order to quantify any associated cell toxicity. This identified 100 compounds with IC(50)'s less than 50 muM. A-33903 (18), a 1,4-benzodiazepine analogue, was chosen as the starting point for lead optimization. This molecule was moderately active and demonstrated good pharmacokinetic properties. The most potent compounds identified from this work were A-58568 (47), A-58569 (44), and A-62066 (46), where modifications to the aromatic substitution enhanced potency, and A-58175 (42), where the amide linker was modified.
