RESUMO
Two series of 5-aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, 5g was found to have the best PTP1B inhibitory potency (IC50 = 2.66 ± 0.16 µM) and the best cell division cycle 25 homolog B (CDC25B) inhibitory potency (IC50 = 0.25 ± 0.02 µM). Enzymatic data together with molecular modeling results demonstrated that the introduction of a sec-butyl group at the 2-position of the carboxyl group remarkably improved the PTP1B inhibitory activity.
Assuntos
Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Isoleucina/farmacologia , Fenilalanina/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Rodanina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Furanos/síntese química , Furanos/química , Humanos , Isoleucina/química , Estrutura Molecular , Fenilalanina/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Rodanina/química , Relação Estrutura-AtividadeRESUMO
A series of (E)-2-(4-cinnamylpiperazin-1-yl)-N-(1-substituted-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume on isolated rabbit heart preparations. This class of compounds presented favorable in vitro activity compared with the standard drug, milrinone, among which N-(1-(3-chlorophenyl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(4-cinnamylpiperazin-1-yl)acetamide 5e was found to be the most potent with 16.58 ± 0.11% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10(-5) M. The chronotropic effects of the compounds having inotropic effects were also evaluated.
Assuntos
Acetamidas/síntese química , Função do Átrio Esquerdo/efeitos dos fármacos , Cardiotônicos/síntese química , Átrios do Coração/efeitos dos fármacos , Quinolinas/síntese química , Triazóis/síntese química , Acetamidas/química , Acetamidas/farmacologia , Animais , Cardiotônicos/química , Cardiotônicos/farmacologia , Técnicas In Vitro , Estrutura Molecular , Quinolinas/química , Quinolinas/farmacologia , Coelhos , Volume Sistólico/efeitos dos fármacos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
Two series of N-(1-oxo-1,2,4,5-tetrahydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides bearing piperazine and 1,4-diazepane moieties were synthesized and screened for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. Most of the derivatives exhibited better in vitro positive inotropic activity than the existing drug, milrinone, among which 2-(4-(4-chlorobenzyl)-1,4-diazepan-1-yl)-N-(1-oxo-1,2,4,5-tetrahydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide 6c proved to be the most potent with 15.48 ± 0.27% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10(-5) M. The chronotropic effects of the compounds that exhibited inotropic effects were also evaluated.
