RESUMO
We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing.
Assuntos
Inibidores do Fator Xa , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Pró-Fármacos/química , Inibidores de Serina Proteinase/química , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.
Assuntos
Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Inibidores dos Fatores de Coagulação Sanguínea/síntese química , Fator VIIa/antagonistas & inibidores , Lipoproteínas/síntese química , Metilaminas/síntese química , Metilaminas/farmacologia , Tromboplastina/antagonistas & inibidores , Administração Oral , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Inibidores dos Fatores de Coagulação Sanguínea/química , Inibidores dos Fatores de Coagulação Sanguínea/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Ligantes , Lipoproteínas/química , Lipoproteínas/farmacologia , Macaca fascicularis , Masculino , Metilaminas/química , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Estrutura Secundária de Proteína , Sensibilidade e Especificidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We examined the antithrombotic and thrombolytic effects of the G(q/11) inhibitor YM-254890 in an electrically-induced carotid artery thrombosis model in rats. YM-254890 dose-dependently inhibited ex vivo ADP-induced platelet aggregation after i.v. bolus injection. In the thrombosis study, YM-254890 dosedependently prolonged time to occlusion at doses of 3 and 10 g/kg i.v. and decreased occlusion rate at 10 g/kg i.v. In the thrombolysis study, YM-254890 at 30 micro g/kg i.v. shortened the time to reperfusion and prevented reocclusion after thrombolysis with a modified tissue-type plasminogen activator. YM-254890, at 10 micro g/kg and more, significantly improved carotid patency status after thrombolysis. However, at 30 micro g/kg and more, YM-254890 decreased systemic blood pressure. These results suggest that YM-254890 may be effective for treating G(q)-mediated diseases, and that YM-254890 is a useful tool for investigating the biological roles of G(q/11).