10.1021/ml400526d.s001
Leifeng Cheng
Leifeng
Cheng
Daniel Pettersen
Daniel
Pettersen
Bengt Ohlsson
Bengt
Ohlsson
Peter Schell
Peter
Schell
Michael Karle
Michael
Karle
Emma Evertsson
Emma
Evertsson
Sara Pahlén
Sara
Pahlén
Maria Jonforsen
Maria
Jonforsen
Alleyn T. Plowright
Alleyn T.
Plowright
Jonas Boström
Jonas
Boström
Tomas Fex
Tomas
Fex
Anders Thelin
Anders
Thelin
Constanze Hilgendorf
Constanze
Hilgendorf
Yafeng Xue
Yafeng
Xue
Göran Wahlund
Göran
Wahlund
Walter Lindberg
Walter
Lindberg
Lars-Olof Larsson
Lars-Olof
Larsson
David Gustafsson
David
Gustafsson
Discovery of the Fibrinolysis Inhibitor AZD6564, Acting
via Interference of a Protein–Protein Interaction
American Chemical Society
2014
plasmin
series
DMPK properties
Interference
plasma clotlysis assays
Acting
Fibrinolysi
human
protein
dosing
isoxazolone
0.44 μ M
permeability
lysine binding site
lysine mimetics
crystallography
fibrinolysis inhibitors
dose
GABAa selectivity
340 mg
carboxylic acid isostere
inhibitors bind
interaction
potency
Inhibitor
AZD
Optimization
Protein
plasma clot lysis IC 50
InteractionA
2014-05-08 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Discovery_of_the_Fibrinolysis_Inhibitor_AZD6564_Acting_via_Interference_of_a_Protein_Protein_Interaction/2298946
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 (<b>19</b>) displaying an in
vitro human plasma clot lysis IC<sub>50</sub> 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.