RESUMO
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.
Assuntos
Inibidores do Fator Xa , Fibrinolíticos/síntese química , Isoquinolinas/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Tetra-Hidroisoquinolinas/síntese química , Administração Oral , Animais , Arteriopatias Oclusivas/complicações , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/etiologia , Infarto Encefálico/patologia , Doenças Arteriais Cerebrais/complicações , Fator Xa/química , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Injeções Intravenosas , Isoquinolinas/química , Isoquinolinas/farmacologia , Macaca fascicularis , Artéria Cerebral Média , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Trombose Venosa/tratamento farmacológicoRESUMO
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against FXa and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis.
Assuntos
Inibidores do Fator Xa , Inibidores de Serina Proteinase/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Ratos , Inibidores de Serina Proteinase/uso terapêutico , Tetra-Hidroisoquinolinas/uso terapêutico , Trombose Venosa/tratamento farmacológico , Trombose Venosa/enzimologiaRESUMO
A series of benzimidazole derivatives with the side chain on the nitrogen atom oriented to the prime site of factor Xa (FXa) were designed and synthesized. Compounds with substituted aminocarbonylmethyl groups as the side chain showed potent FXa inhibitory activity. Compounds 1 and 2 exhibited most potent inhibitory activity and were effective as anticoagulants in a DIC model.
