RESUMEN
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.
Asunto(s)
Anticoagulantes/síntesis química , Compuestos Aza/síntesis química , Bencimidazoles/síntesis química , Indoles/síntesis química , Trombina/antagonistas & inhibidores , Aminas/síntesis química , Aminas/química , Aminas/farmacología , Anticoagulantes/química , Anticoagulantes/farmacología , Compuestos Aza/química , Compuestos Aza/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Diseño de Fármacos , Indoles/química , Indoles/farmacología , Cinética , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Anticoagulantes/síntesis química , Pirrolidinas/síntesis química , Inhibidores de Serina Proteinasa/síntesis química , Tiofenos/síntesis química , Trombina/antagonistas & inhibidores , Animales , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/farmacología , Trombosis/sangre , Trombosis/metabolismoRESUMEN
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.
Asunto(s)
Tiofenos/química , Trombina/antagonistas & inhibidores , Animales , Anticoagulantes/química , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Humanos , Modelos Moleculares , Ratas , Relación Estructura-Actividad , Tiofenos/farmacología , Tiofenos/uso terapéutico , Trombina/química , Trombosis/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Antitrombinas/farmacología , Tiofenos/farmacología , Antitrombinas/química , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Tiofenos/químicaRESUMEN
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.