Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction.

A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 µM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.

Melagatran attenuates fibrin and platelet deposition in a porcine coronary artery over-stretch injury model.

Melagatran is the active form of the oral direct thrombin inhibitor, ximelagatran. The purpose of this study was to compare the effects of different doses of melagatran with heparin or placebo on platelet deposition and relative fibrin content after coronary angioplasty in pigs. After 125I-labelled fibrinogen and autologous 111Indium-labelled platelets had been infused a balloon injury was performed in the left anterior descending and the right coronary arteries. Pigs were randomized to receive either heparin 200 IU/kg bolus plus 20 IU/kg per h infusion (n = 7); melagatran 1 mg/kg bolus plus 0.33 mg/kg per h infusion (n = 7); melagatran bolus 0.5 mg/kg plus 0.17 mg/kg per h infusion (n = 7); melagatran 0.15 mg/kg bolus plus 0.05 mg/kg per h infusion (n = 6) or saline (n = 4). Seventy-five minutes after the angioplasty, the pigs were euthanized and the injured vessel segments were measured in a gamma counter. Compared with placebo, platelet deposition and relative fibrin content were reduced after both heparin and melagatran, in the latter case with a dose-response relationship. Melagatran reduced platelet deposition and relative thrombus size in a dose-dependent manner when compared with placebo after coronary angioplasty in pigs. No statistically significant difference between melagatran and heparin was found.