RESUMO
In the course of development of factor Xa (FXa) inhibitor in an investigation involving the synthesis of 1-arylsulfonyl-3-piperazinone derivatives, we found new compounds containing a unique spiro skeleton. Among such compounds, (-)-7-[(6-chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-1'-(4-pyridinyl)-spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one (28, M55529) had activity more favorable than those of previously reported compounds. The inhibitory activity of M55529 for FXa is IC(50)=2 nM, with high selectivity for FXa over thrombin and trypsin.
Assuntos
Inibidores do Fator Xa , Piridinas/síntese química , Piridinas/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Cristalografia por Raios X , Ciclização , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/farmacologiaRESUMO
Intravascular clot formation is an important event in a number of cardiovascular diseases. The prevention of blood coagulation has become a major target for new therapeutic agents. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. We have investigated substituents in the central part of a lead compound (3: M55113), and discovered that compound M55551 (34: (R)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic acid) is a potent inhibitor of FXa (IC(50)=0.006 microM), with high selectivity for FXa over trypsin and thrombin. The activity of this compound is ten times more powerful than the lead compound.