title: Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction.
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.
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Leifeng
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pettersen
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Ohlsson
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Schell
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Karle
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Evertsson
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Pahlén
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Jonforsen
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Alleyn T
authors.initials: AT
authors.lastname: Plowright
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Boström
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Fex
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Thelin
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hilgendorf
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Wahlund
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Walter
authors.initials: W
authors.lastname: Lindberg
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Larsson
authors.affiliation: Medicinal Chemistry, CVMD iMED, Bioscience, CVMD iMED, DMPK, CVMD iMED, and Discovery Sciences, AstraZeneca Mölndal , SE-43183 Mölndal, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Gustafsson
keywords: Fibrinolysis; inhibitor; isoxazolone; plasminogen; protein−protein interaction; tranexamic acid