Initial identification of fXa inhib

Initial identification of fXa inhibitors relied on high throughput screening assays based on inhibition of fXa induced chromogenic or clotting activity the first leads contained isoxazole derivatives such as benzamidine guanidine or napthylamine which are thought to mimic Glu-Gly-Arg the sequence in prothrombin that is recognized by fXa the first such compound was Dx-9065a which contained highly basic amidine groups as non peptidic mimetic of the Arg residue in the prothrombin recognition sequence because it exploited interactions with the S4 and S1 subsites of the active site ( figure 2) DX-9065a was specific for fXa and inhibited the enzyme with a K value of 46 nmol/l. After establishing its antithrombotic activity in a variety of animal models of venous and arterial thrombosis DX-9065a was compared with heparin in a small phase II dose-finding study in ACS patients. Although the results of the study were promising development of DX-9065a was halted because the oral bioavailability of the drug in humans was only 2 % to 3% because of its highly basic amidine content . 42 Nonetheless DX-9065a provided the groundwork future orally active fXa inhibitors

ผลลัพธ์ (อังกฤษ) 1:

Initial identification of fXa inhibitors relied on high throughput screening assays based on inhibition of fXa induced chromogenic or clotting activity the first leads contained isoxazole derivatives such as benzamidine guanidine or napthylamine which are thought to mimic Glu-Gly-Arg the sequence in prothrombin that is recognized by fXa the first such compound was Dx-9065a which contained highly amidine groups as non peptidic mimetic of the Arg residue in the prothrombin recognition sequence because it exploited interactions with the S4 and S1 subsites of the active site ( figure 2) DX-9065a was specific for fXa and inhibited the enzyme with a K value of 46 nmol/l. After establishing its antithrombotic activity in a variety of animal models of venous and arterial thrombosis DX-9065a was compared with heparin in a small phase II dose-finding study in ACS patients. Although the results of the study were promising development of DX-9065a was halted because the oral bioavailability of the drug in humans was only 2 % to 3% because of its highly basic amidine content . 42 Nonetheless DX-9065a provided the groundwork future orally active fXa inhibitors