RESUMO
RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.
Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Descoberta de Drogas , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica , Proteínas Virais de Fusão/metabolismoRESUMO
A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed.
Assuntos
Indóis/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Indóis/síntese química , Indóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of quinoxaline inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and optimisation of the series was performed on the basis of this structure. Future directions for development of the series are discussed together with the identification of a novel quinoline scaffold.