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Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein–Protein Interaction
journal contribution
posted on 2014-05-08, 00:00 authored 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 GustafssonA 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.
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plasminseriesDMPK propertiesInterferenceplasma clotlysis assaysActingFibrinolysihumanproteindosingisoxazolone0.44 μ Mpermeabilitylysine binding sitelysine mimeticscrystallographyfibrinolysis inhibitorsdoseGABAa selectivity340 mgcarboxylic acid isostereinhibitors bindinteractionpotencyInhibitorAZDOptimizationProteinplasma clot lysis IC 50InteractionA
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