2. Academic Validation
  3. Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction

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

  • ACS Med Chem Lett. 2014 Feb 18;5(5):538-43. doi: 10.1021/ml400526d.
Leifeng Cheng 1,  Daniel Pettersen 1,  Bengt Ohlsson 1,  Peter Schell 1,  Michael Karle 1,  Emma Evertsson 1,  Sara Pahlén 1,  Maria Jonforsen 1,  Alleyn T Plowright 1,  Jonas Boström 1,  Tomas Fex 1,  Anders Thelin 1,  Constanze Hilgendorf 1,  Yafeng Xue 1,  Göran Wahlund 1,  Walter Lindberg 1,  Lars-Olof Larsson 1,  David Gustafsson 1
Affiliations

Affiliation

  • 1 Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
PMID: 24900876 DOI: 10.1021/ml400526d
Abstract

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.

Keywords

Fibrinolysis; inhibitor; isoxazolone; plasminogen; protein−protein interaction; tranexamic acid.

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  • HY-12586
    纤维蛋白溶解抑制剂
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