RESUMO
5(S)-Fluoro-N6-(iminoethyl)-l-lysine (14), an analogue of the potent, selective induced nitric oxide synthase (iNOS) inhibitor iminoethyl-l-lysine (1), was synthesized and found to be a selective iNOS inhibitor.
Assuntos
Lisina/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Cristalografia por Raios X , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Lisina/análogos & derivados , Lisina/química , Modelos Moleculares , Óxido Nítrico Sintase/química , Óxido Nítrico Sintase Tipo IIRESUMO
In the literature, the introduction of fluorine into bioactive molecules has been known to enhance the biological activity relative to the parent molecule. Described in this article is the synthesis of 4R-fluoro-L-NIL (12) and 4,4-difluoro-L-NIL (23) as part of our iNOS program. Both 12 and 23 were found to be selective iNOS inhibitors as shown in Table 2 below. Secondarily, methodology to synthesize orthogonally protected 4-fluoro-L-lysine and 4,4-difluoro-L-lysine has been developed.
Assuntos
Inibidores Enzimáticos/química , Flúor/química , Lisina/análogos & derivados , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Cristalografia por Raios X , Humanos , Lisina/química , Camundongos , Modelos Biológicos , Modelos Químicos , Estrutura Molecular , Óxido Nítrico Sintase Tipo IIRESUMO
(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.
