RESUMO
A novel series of 1,2-disubstituted indole, azaindole and benzimidazole derivatives possessing an amine moiety was identified as thrombin inhibitors. An indole with basic diamine moieties (12a) was the most potent thrombin inhibitor in the series with Kass= 197 x 10(6) L/mol.
Assuntos
Anticoagulantes/síntese química , Compostos Aza/síntese química , Benzimidazóis/síntese química , Indóis/síntese química , Trombina/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Anticoagulantes/química , Anticoagulantes/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Cinética , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
Assuntos
Anticoagulantes/síntese química , Pirrolidinas/síntese química , Inibidores de Serina Proteinase/síntese química , Tiofenos/síntese química , Trombina/antagonistas & inibidores , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/farmacologia , Trombose/sangue , Trombose/metabolismoRESUMO
Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.
Assuntos
Tiofenos/química , Trombina/antagonistas & inibidores , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Trombina/química , Trombose/tratamento farmacológicoRESUMO
The preparation and biological evaluation of a series of benzo[b]thiophene diamine thrombin inhibitors possessing conformationally restricted C-4" linkers are reported. Compared to the parent compounds 1a/b, the unsaturated derivatives 3a/b exhibited a modest twofold increase in thrombin inhibitory activity, while the more lipophilic carbocyclic ring containing analogs 4a/b affected an eightfold enhancement in potency.
Assuntos
Antitrombinas/farmacologia , Tiofenos/farmacologia , Antitrombinas/química , Sítios de Ligação , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Tiofenos/químicaRESUMO
The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.