RESUMEN
A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC50 values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC50 in the low nanomolar range.
Asunto(s)
Antivirales/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Hepacivirus/química , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Línea Celular Tumoral , Humanos , Imidazoles/síntesis química , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.
Asunto(s)
Antivirales/química , Hepacivirus/metabolismo , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Antivirales/metabolismo , Antivirales/farmacología , Antivirales/uso terapéutico , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C/patología , Hepatitis C/virología , Humanos , Mutación , Pargilina/química , Pirazinas/química , Relación Estructura-Actividad , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Studies on the relationship between the structure of the benzene moiety of S-(2-(acylamino)phenyl) 2,2-dimethylpropanethioates and CETP inhibitory activity were performed. Substituents on the benzene moiety influenced CETP inhibitory activity in a type and position dependent manner, and electron-withdrawing groups at the 4- or 5-position increased the activity. The most potent compound showed 50% inhibition of CETP activity in human plasma at a concentration of 2 microM.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Glicoproteínas/antagonistas & inhibidores , Compuestos de Sulfhidrilo/farmacología , Amidas , Arteriosclerosis/prevención & control , Proteínas Portadoras/sangre , Proteínas de Transferencia de Ésteres de Colesterol , HDL-Colesterol/agonistas , Ésteres , Glicoproteínas/sangre , Humanos , Concentración 50 Inhibidora , Sustancias Protectoras/síntesis química , Sustancias Protectoras/farmacología , Quinolinas , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/síntesis químicaRESUMEN
A series of 4-aryl/cycloalkyl-5-phenyloxazole derivatives was synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). These compounds were found to be potent and selective COX-2 inhibitors.