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1.
Eur J Med Chem ; 38(3): 277-88, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12667694

RESUMO

A series of 2-iminopiperidines fused to small-membered rings (Tables 1 and 2) were synthesised and biologically evaluated using an in vitro human nitric oxide synthase (NOS) inhibition assay. Fused bicyclic compounds 5-9 exhibited nearly the same potency as compound 1 in the hiNOS inhibition assay. Among these, the 1-methyl analogues 8 and 9 showed better isoform selectivity than their corresponding unsubstituted analogues 7 and 6, respectively. Compounds 5 and 6 were also evaluated by an in vivo NO accumulation assay in a mouse model. The discovery process of new chemical leads for an orally bioavailable inhibitor of human inducible NOS (iNOS) is reported. The structure-activity relationship (SAR) study and chemistry of these compounds are also reported.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Piperidinas/síntese química , Piperidinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Desenho de Fármacos , Inibidores Enzimáticos/toxicidade , Humanos , Indicadores e Reagentes , Isoenzimas/antagonistas & inibidores , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II , Proteínas Recombinantes/efeitos dos fármacos , Relação Estrutura-Atividade , Especificidade por Substrato , ômega-N-Metilarginina/farmacologia
2.
J Org Chem ; 67(3): 640-7, 2002 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-11856001

RESUMO

The reaction of the alpha-carbanion derived from (trimethylsilyl)vinyl sulfoxides with aldehydes afforded a diastereomeric mixture of the products. Each diastereomer was subjected to specific elimination reactions to give optically pure propargylic, trimethylsilylated propargylic, and allylic alcohols. Acceleration of the sulfenic acid-elimination from the beta-silylvinyl sulfoxide was demonstrated by the ab initio calculation to be ascribed mainly to the beta-effect of the silyl group.

3.
Bioorg Med Chem ; 11(8): 1723-43, 2003 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-12659759

RESUMO

Further chemical modification of 2-iminopiperidines fused to cyclopropane rings was performed. Optically active isomers 2 and 13 were synthesized and their biological activity was evaluated. Compound 2 exhibited greater potency and more isoform selectivity than enantiomer 13 in the iNOS inhibition assay. One of the gem-chlorines on the fused cyclopropane moiety of 2 was eliminated to produce 3, which showed reduced potency for iNOS inhibition, as well as 4 with an increased potency. The isoform selectivity of 4 was also much higher than that of 3. This was also true for the corresponding methyl derivatives 6-9. The structure-activity relationship (SAR) study and computer aided docking study of the most optimized structure 4 with human iNOS will also be reported.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Iminas/síntese química , Iminas/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Disponibilidade Biológica , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/toxicidade , Cristalografia por Raios X , Ciclopropanos/síntese química , Ciclopropanos/química , Ciclopropanos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/toxicidade , Humanos , Iminas/química , Iminas/toxicidade , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , ômega-N-Metilarginina/farmacologia
4.
Bioorg Med Chem ; 11(5): 689-702, 2003 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-12537998

RESUMO

The process of discovery and biological evaluation of alpha,beta-unsaturated cyclic amidines, as selective inhibitors of inducible nitric oxide synthase (iNOS), is reported. Dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide synthase inhibition assay. Compounds 1, 5, 6, 8-12 and 16 exhibited potent inhibition of iNOS. Among these, compounds 6, 7, 10, 11 and 16 showed 5- to 19-fold isoform selectivity. Compounds 1, 6, 10, 11 and 16 also showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 6 showed excellent bioavailability (BA) in rats when administered orally. Full details are presented here, including the structure-activity relationship (SAR) studies, the chemistry of these compounds, and the pharmacokinetic data and the computer-aided docking study of 10 with hiNOS.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Iminas/síntese química , Iminas/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Animais , Disponibilidade Biológica , Simulação por Computador , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Indicadores e Reagentes , Injeções Intravenosas , Isoenzimas/antagonistas & inibidores , Cinética , Espectrometria de Massas , Camundongos , Modelos Moleculares , Conformação Molecular , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II , Ratos , Proteínas Recombinantes/química , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 12(17): 2291-4, 2002 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-12161118

RESUMO

Dihydropyridin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide inhibition assay. Compounds 1, 4, 5 and 7-11 exhibited potent activity in the inducible nitric oxide (iNOS) inhibition assay. Of these 5, 6, 9 and 10 showed 5- to 11-fold increases in isoform selectivity. Compounds 1, 5, 9 and 10 showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 5 also showed good bioavailability (BA) when given orally.


Assuntos
Di-Hidropiridinas/farmacocinética , Inibidores Enzimáticos/farmacocinética , Óxido Nítrico Sintase/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Iminas/síntese química , Iminas/farmacocinética , Iminas/farmacologia , Lipopolissacarídeos/administração & dosagem , Dose Máxima Tolerável , Camundongos , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo II , Relação Estrutura-Atividade
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