RESUMEN
Extensive SAR studies and optimization of ADME properties of benzimidazol-2-one derivatives led to the identification of BMS-433771 (3) as an orally active RSV fusion inhibitor. In order to extend the structure-activity relationships for this compound series, substitution of the benzimidazole ring was examined with a view to establishing additional productive interactions between the inhibitor and functionality present in the proposed binding pocket. Amongst the compounds synthesized, the 5-aminomethyl analogue 10aa demonstrated potent antiviral activity towards wild-type RSV and retained excellent inhibitory activity towards a virus that had been developed to express resistance to BMS-433771 (3), data consistent with an additional productive interaction between the inhibitor and the fusion protein target.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Bencimidazoles/química , Virus Sincitiales Respiratorios/efectos de los fármacos , Línea Celular Tumoral , Humanos , Modelos Moleculares , Estructura Molecular , Mutación , Virus Sincitiales Respiratorios/genética , Virus Sincitiales Respiratorios/metabolismo , Relación Estructura-Actividad , Replicación ViralRESUMEN
The introduction of acidic and basic functionality into the side chains of respiratory syncytial virus (RSV) fusion inhibitors was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. The acidic compounds 2r, 2u, 2v, 2w, 2z, and 2aj demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the oxadiazolone 2aj reduced virus titers following subcutaneous dosing, whilst the ester 2az and amide 2aab exhibited efficacy following oral administration. These results established the potential of this class of RSV fusion inhibitors to interfere with infection in vivo following topical or systemic administration.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Fusión de Membrana/efectos de los fármacos , Virus Sincitiales Respiratorios/efectos de los fármacos , Virus Sincitiales Respiratorios/fisiología , Agua/química , Aminas/química , Animales , Antivirales/efectos adversos , Antivirales/síntesis química , Bencimidazoles/efectos adversos , Bencimidazoles/síntesis química , Ratones , Estructura Molecular , Ratas , Sigmodontinae , Solubilidad , Relación Estructura-ActividadRESUMEN
Structure-activity relationships for a series of benzimidazol-2-one-based inhibitors of respiratory syncytial virus are described. These studies focused on structural variation of the benzimidazol-2-one substituent, a vector inaccessible in a series of benzotriazole derivatives on which 2 is based, and revealed a broad tolerance for substituent size and functionality.