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J Med Chem ; 50(7): 1685-92, 2007 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-17341059

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 Viral
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