RESUMO
Thrombin is a serine protease that plays a key role in blood clotting, which makes it a promising target for the treatment of thrombotic diseases. Dabigatran is direct potent thrombin inhibitor. Based on bioisosteric and scaffold hopping principle, two dabigatran mimics (I-1 and II-1) in which the benzamidine moiety of dabigatran was replaced by a tricyclic fused scaffold were designed, synthesized and evaluated for their in vitro activities for inhibiting thrombin. The results reveal that compounds I-1 (IC50=9.20nM) and II-1 (IC50=7.48nM) are potent direct thrombin inhibitors and the activity is in the range of reference drug. On this basis, twenty-two ester and carbamate derivatives of I-1 or II-1 were prepared and evaluated for their anticoagulant activity. Prodrugs I-4a (IC50=0.73µM), I-4b (IC50=0.75µM), II-2a (IC50=1.44µM) and II-2b (IC50=0.91µM) display excellent effects of inhibiting thrombin induced-platelet aggregation. Moreover, compounds I-9 and II-4, which contain a cleavable moiety with anti-platelet activity, show the best anticoagulant efficacy among the tested compounds in the rat venous thrombosis model. The compounds which have better in vitro and in vivo activity were subjected to rat tail bleeding test, and the result demonstrates that compound I-9 is less likely to have bleeding risk than dabigatran etexilate.
Assuntos
Anticoagulantes/farmacologia , Dabigatrana/análogos & derivados , Dabigatrana/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Trombina/antagonistas & inibidores , Animais , Anticoagulantes/síntese química , Anticoagulantes/química , Dabigatrana/síntese química , Dabigatrana/química , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
A novel series of prodrugs containing dabigatran and methyl (E)-3-(4-hydroxy-2-methoxyphenyl)propenoate (methyl ferulate) were synthesized. All of them reveal the effect of thrombin-induced anti-platelet aggregation in vitro. In addition, in vivo experiment shows that one of the target compounds, X-2 (ED50=3.7 ± 1.0 µmol/kg) possesses a more potent activity for inhibiting venous thrombosis than that of dabigatran etexilate (ED50=7.8 ± 1.5 µmol/kg).
Assuntos
Desenho de Fármacos , Fibrinolíticos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pró-Fármacos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Ácidos Cafeicos/química , Dabigatrana , Relação Dose-Resposta a Droga , Fibrinolíticos/síntese química , Fibrinolíticos/química , Humanos , Estrutura Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Piridinas/farmacologia , Trombina/metabolismo , Trombose Venosa/tratamento farmacológico , beta-Alanina/análogos & derivados , beta-Alanina/químicaRESUMO
A novel series of prodrugs consisting of dabigatran and 2-hydroxymethyl-3,5,6-trimethylpyrazine (HTMP) were synthesized. The pharmacological results show that all of them possess the effect of anti-platelet aggregation induced by thrombin in vitro. Moreover, one of those compounds, Y-2 (ED(50) = 2.1 ± 1.3 mg/kg) shows more potent activity for inhibiting thrombosis in vivo than that of dabigatran etexilate (ED(50) = 4.4 ± 2.2 mg/kg).
