RESUMO
(3S,4S,5R)-2-Imino-4-methyl-5-pentyl-3-pyrrolidinol hydrochloride (1) is a potent inducible nitric oxide synthase (i-NOS) inhibitor that has three times the selectivity of its parent, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine hydrochloride (2).
Assuntos
Óxido Nítrico Sintase/antagonistas & inibidores , Pirrolidinas/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Iminas/síntese química , Iminas/química , Iminas/farmacologia , Concentração Inibidora 50 , Isoenzimas/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II , Pirrolidinas/química , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The 5-tetrazole amide of L-N(6)-(1-iminoethyl)lysine (L-NIL), L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (1), has been prepared and evaluated. In contrast to L-NIL, 1 is a stable, nonhygroscopic, crystalline solid. Unlike L-NIL, 1 has minimal inhibitory activity in vitro on human inducible nitric oxide synthase (iNOS). However, it is rapidly converted in vivo to L-NIL and produces dose-dependent inhibition of iNOS in acute and chronic models of inflammation in the rodent with efficacy comparable to L-NIL. In addition, both 1 and L-NIL exhibit significant and comparable in vivo selectivity for the inhibition of iNOS vs endothelial NOS. Doses approximately 80-fold greater than those that inhibited inflammation do not elevate systemic blood pressure. In summary, both the physical properties and the pharmacological profile of 1 make it an ideal molecule for preclinical and clinical studies on the role of selective iNOS inhibitors in mediating inflammatory disease processes.