RESUMO
Design, synthesis and biochemical evaluation of a series of novel non-covalent thrombin inhibitors with a 1-amidinopiperidine moiety are presented. Replacement of the planar benzamidine group in azaphenylalanine derivatives with 1-amidinopiperidine resulted in lower activity but higher selectivity for this type of compounds. The binding conformation of inhibitors in the active site of thrombin was revealed by molecular modelling studies.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Trombina/antagonistas & inibidores , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea , Desenho de Fármacos , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Espectrofotometria Infravermelho , Tempo de Trombina , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/química , Inibidores da Tripsina/farmacologiaRESUMO
Design, synthesis and biological evaluation of a series of novel non-covalent azaphenylalanine thrombin inhibitors are presented. Replacement of the basic benzamidine moiety in azaphenylalanine derivatives by benzylamine (P1 part of a molecule) and the introduction of a N-cyclopentyl-N-methylamine moiety in the P2 part of a molecule resulted in the thrombin inhibitor LK-733 with greatly increased selectivity against trypsin and an in vitro Ki of 31 nM.
Assuntos
Hidrazinas/síntese química , Hidrazinas/farmacologia , Fenilalanina/análogos & derivados , Trombina/antagonistas & inibidores , Sítios de Ligação , Inibidores do Fator Xa , Indicadores e Reagentes , Cinética , Espectroscopia de Ressonância Magnética , Fenilalanina/síntese química , Fenilalanina/farmacologia , Inibidores de Serina Proteinase , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/farmacologiaRESUMO
New inhibitors of serine proteases with azaphenylalanine scaffold were synthesized and their activity was evaluated in vitro. We studied the effect of different substituents in the part of a molecule that binds in the distal pocket of the thrombin active site. Modifications generally led to decreased activity, however two derivatives are promising lead compounds as new thrombin and dual thrombin-factor Xa inhibitors.