RESUMO
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
The discovery of a highly potent and selective tissue factor/factor VIIa inhibitor is described. Upon oral administration of its double prodrug in the guinea pig, a dose-dependent antithrombotic effect is observed in an established model of arterial thrombosis without prolonging bleeding time. The pharmacodynamic properties of this selective inhibitor are compared to the behaviour of a mixed factor VIIa/factor Xa inhibitor.