Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase.
Bioorg Med Chem
; 21(5): 1333-43, 2013 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-23352768
ABSTRACT
Inhibitors of neuronal nitric oxide synthase have been proposed as therapeutics for the treatment of different types of neurological disorders. On the basis of a cis-3,4-pyrrolidine scaffold, a series of trans-cyclopropyl- and methyl-containing nNOS inhibitors have been synthesized. The insertion of a rigid electron-withdrawing cyclopropyl ring decreases the basicity of the adjacent amino group, which resulted in decreased inhibitory activity of these inhibitors compared to the parent compound. Nonetheless, three of them exhibited double-digit nanomolar inhibition with high nNOS selectivity on the basis of in vitro enzyme assays. Crystal structures of nNOS and eNOS with these inhibitors bound provide a basis for detailed structure-activity relationship (SAR) studies. The conclusions from these studies will be used as a guide in the future development of selective NOS inhibitors.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Ciclopropanos
/
Inibidores Enzimáticos
/
Óxido Nítrico Sintase Tipo I
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos