RESUMO
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.
Assuntos
Inibidores Enzimáticos/química , Isoxazóis/química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Piridinas/química , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estrutura Terciária de Proteína , Piridinas/farmacologia , RatosRESUMO
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.
Assuntos
Aminopiridinas/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Aminopiridinas/química , Animais , Cristalografia por Raios X , Camundongos , Modelos Moleculares , Óxido Nítrico Sintase/química , Óxido Nítrico Sintase Tipo IIRESUMO
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.