RESUMO
There is considerable evidence that excessive nitric oxide (NO) synthesized from L-arginine by inducible nitric oxide synthase (iNOS) plays an important pathological role in inflammatory arthritis. Since NO synthesized by constitutive isoforms of NOS has a physiological role, a great deal of activity has been directed at identifying inhibitors of NOS that are selective for the induced isoform. The major chemical areas that have been described so far in the search for such selective iNOS inhibitors and the activity of some of these compounds in animal models of arthritis are reviewed.
RESUMO
3-Phenyl-3.4-dihydro-1-isoquinolinamine is a weak inhibitor of iNOS and nNOS. Structural variation of 5a results in inhibitors with a range of potency and selectivity for the NOS enzymes, including a potent and very selective iNOS inhibitor 5j.
Assuntos
Inibidores Enzimáticos/farmacologia , Isoquinolinas/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Células Cultivadas , Cerebelo/citologia , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Isoformas de Proteínas/antagonistas & inibidores , Ratos , Sensibilidade e EspecificidadeRESUMO
5-Substituted 7-amino-4,5-tetrahydrothieno[2,3-c]pyridines and 6-substituted 4-amino-6,7-dihydrothieno[3,2-c]pyridines were shown to be exceptionally potent inhibitors of inducible and neuronal nitric oxide synthase. Selectivity and potency could be modulated by variation of the 5- or 6-substituent. Compound 3e showed potent in vivo inhibition of iNOS.