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

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journal contribution
posted on 08.05.2014 by Leifeng Cheng, Daniel Pettersen, Bengt Ohlsson, Peter Schell, Michael Karle, Emma Evertsson, Sara Pahlén, Maria Jonforsen, Alleyn T. Plowright, Jonas Boström, Tomas Fex, Anders Thelin, Constanze Hilgendorf, Yafeng Xue, Göran Wahlund, Walter Lindberg, Lars-Olof Larsson, David Gustafsson
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.