RESUMO
Butadiene-imide 1 (T-686) derivatives were synthesized and evaluated for their inhibitory activity against PAI-1 production and their ADMET (DMPK and toxicology) profiles. Among these derivatives, compound 15k (T-2639) showed good antithrombotic activity in two rat thrombosis models without affecting bleeding time, indicating reduction of haemorrhagic risk. We also describe in this report a practical synthesis of 15k suitable for scale-up using Z,E-selective Stobbe condensation.
Assuntos
Butadienos/química , Butadienos/síntese química , Fibrinolíticos/síntese química , Fenilbutiratos/síntese química , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inibidores de Serina Proteinase/síntese química , Administração Oral , Animais , Butadienos/farmacocinética , Butadienos/uso terapêutico , Células Cultivadas , Cristalografia por Raios X , Cães , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Conformação Molecular , Fenilbutiratos/química , Fenilbutiratos/uso terapêutico , Ratos , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-AtividadeRESUMO
We describe in this Letter a new synthetic method for pyrrolin-2-ones as potent plasminogen activator inhibitor-1 (PAI-1) inhibitors. Pyrrolin-2-one derivatives synthesized from N-2-oxoethylamides and aldehydes in aqueous NaOH by one-pot were evaluated for their PAI-1 inhibitory activity. Among these derivatives, compounds 16 and 18 were found to possess potent PAI-1 inhibitory activity (compound 16: IC(50): 0.69microM, compound 18: IC(50): 0.65microM).
Assuntos
Acrilatos/síntese química , Fibrinolíticos/síntese química , Inibidor 1 de Ativador de Plasminogênio/química , Pirrolidinonas/síntese química , Inibidores de Serina Proteinase/química , Acrilatos/química , Acrilatos/farmacologia , Desenho de Fármacos , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Inibidores de Serina Proteinase/metabolismoRESUMO
A novel series of furan-2-one and pyrrolin-2-one derivatives having PAI-1 (plasminogen activator inhibitor-1) inhibitory activity were synthesized and evaluated for their antithrombotic activity in a rat arterial thrombosis model. Among the synthesized compounds, 5f (T-1776Na) was found to have good selectivity for PAI-1 over other enzymes and high antithrombotic activity.
Assuntos
Fibrinolíticos/síntese química , Inibidor 1 de Ativador de Plasminogênio/química , Pirróis/síntese química , Pirrolidinas/síntese química , Animais , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Pirróis/química , Pirróis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A novel series of butadiene-imide 1 (T-686) derivatives having an inhibitory activity against PAI-1 production was synthesized and evaluated their biological activities and DMPK profiles, in which 15k (T-2639) was selected as the best compound based on its strong antithrombotic activity and good bioavailability.
Assuntos
Química Farmacêutica/métodos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Administração Oral , Animais , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/farmacologia , Disponibilidade Biológica , Cães , Vias de Administração de Medicamentos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Químicos , Inibidor 1 de Ativador de Plasminogênio/química , Ratos , Solubilidade , Succinimidas/síntese química , Succinimidas/farmacologiaRESUMO
(E,E)-1,4-Diphenylbutadiene derivatives were synthesized by utilizing the Stobbe reaction of dimethyl succinate as a key step. Their stereoisomers were also synthesized stereoselectively by means of the cross-coupling reaction of the vinylstannanes and the vinylbromides, which were obtained from the propiolic acid esters by stereoselective hydrostannation, as a key step. To discover novel stimulators of fibrinolysis in vascular endothelial cells, the synthesized compounds were added to cultured bovine endothelial cells to determine the activity of the plasminogen activator in the conditioned medium. Of the synthesized compounds, three compounds were found to stimulate the activity of the plasminogen activator in endothelial cells. In addtition, these compounds inhibited thrombus formation in a rat model of venous thrombosis.
Assuntos
Butadienos/química , Butadienos/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Animais , Bovinos , Estrutura Molecular , Ativadores de Plasminogênio/química , Ativadores de Plasminogênio/farmacologia , Relação Estrutura-AtividadeRESUMO
Cis- and trans-isomers of alpha-hydroxy-alpha,beta-dibenzyl-gamma-butyrolactone lignans 1a,d-g and 2a,c,d were stereoselectively synthesized in good yields based on the electrophilic addition to the metal enolate of alpha-benzyl-gamma-butyrolactone derivatives 1l-o and 3 as a key step. This method was applied to the syntheses of (+/-)-trachelogenin and (+/-)-guayadequiol, representative examples of the trans- and cis-isomers of alpha-hydroxy-alpha,beta-dibenzyl-gamma-butyrolactone lignan series.
