RESUMEN
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Asunto(s)
Inhibidores Enzimáticos/química , Isoxazoles/química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Piridinas/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estructura Terciaria de Proteína , Piridinas/farmacología , RatasRESUMEN
The discovery of a novel class of nitric oxide synthase (NOS) inhibitors, 2-substituted 1,2-dihydro-4-quinazolinamines, and the related 4'-aminospiro[piperidine-4,2'(1'H)-quinazolin]-4'-amines is described. Members of both series exhibit nanomolar potency and high selectivity for the inducible isoform of the enzyme (i-NOS) relative to the constitutive isoforms in vitro. Efficacy in acute and chronic animal models of inflammatory disease following oral administration has also been demonstrated using these compounds.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Óxido Nítrico Sintasa/antagonistas & inhibidores , Quinazolinas/síntesis química , Enfermedad Aguda , Administración Oral , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Animales , Artritis Experimental/tratamiento farmacológico , Línea Celular , Enfermedad Crónica , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inyecciones Intravenosas , Isoenzimas/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Quinazolinas/química , Quinazolinas/farmacología , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.