RESUMEN
A series of bezimidazole-isatin oximes were prepared and profiled as inhibitors of respiratory syncytial virus (RSV) replication in cell culture. Structure-activity relationship studies were directed toward optimization of antiviral activity, cell permeability and metabolic stability in human liver micorosomes (HLM). Parallel combinatorial synthetic chemistry was employed to functionalize isatin oximes via O-alkylation which quickly identified a subset of small, lipophilic substituents that established good potency for the series. Further optimization of the isatin oxime derivatives focused on introduction of nitrogen atoms to the isatin phenyl ring to provide a series of aza-isatin oximes with significantly improved PK properties. Several aza-isatin oximes analogs displayed targeted metabolic stability in HLM and permeability across a confluent monolayer of CaCo-2 cells. These studies identified several compounds, including 18i, 18j and 18n that demonstrated antiviral activity in the BALB/c mouse model of RSV infection following oral dosing.
Asunto(s)
Antivirales/química , Isatina/química , Oximas/química , Virus Sincitiales Respiratorios/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacocinética , Células CACO-2 , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The effect of structural variation of the benzimidazol-2-one ring of RSV fusion inhibitors related to BMS-433771 (1) was examined in conjunction with side chain modifications and the introduction of an aminomethyl substituent at the 5-position of the core benzimidazole moiety. Replacement of the benzimidazol-2-one moiety with benzoxazole, oxindole, quinoline-2-one, quinazolin-2,4-dione and benzothiazine derivatives provided a series of potent RSV fusion inhibitors 4. However, the intrinsic potency of 6,6-fused ring systems was generally less than that of comparably substituted 5,6-fused heterocycles of the type found in BMS-433771 (1). The introduction of an aminomethyl substituent to the benzimidazole ring enhanced antiviral activity in the 6,6-fused ring systems.
Asunto(s)
Antivirales/farmacología , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Virus Sincitiales Respiratorios/metabolismo , Proteínas Virales de Fusión/antagonistas & inhibidores , Bencimidazoles/química , Bencimidazoles/farmacología , Química Farmacéutica/métodos , Diseño de Fármacos , Electrones , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Conformación MolecularRESUMEN
A series of benzimidazole-based inhibitors of respiratory syncytial virus (RSV) fusion were optimized for antiviral potency, membrane permeability and metabolic stability in human liver microsomes. 1-Cyclopropyl-1,3-dihydro-3-[[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl]methyl]-2H-imidazo[4,5-c]pyridin-2-one (6m, BMS-433771) was identified as a potent RSV inhibitor demonstrating good bioavailability in the mouse, rat, dog and cynomolgus monkey that demonstrated antiviral activity in the BALB/c and cotton rat models of infection following oral administration.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Animales , Antivirales/farmacocinética , Bencimidazoles/farmacocinética , Disponibilidad Biológica , Células CACO-2 , Fenómenos Químicos , Química Física , Efecto Citopatogénico Viral/efectos de los fármacos , Perros , Semivida , Humanos , Técnicas In Vitro , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/efectos de los fármacos , Ratas , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/virología , Sigmodontinae , Relación Estructura-ActividadRESUMEN
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
In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.