2 research outputs found
Discovery of AZD2716: A Novel Secreted Phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) Inhibitor for the Treatment of Coronary Artery Disease
Expedited
structure-based optimization of the initial fragment hit <b>1</b> led to the design of (<i>R</i>)-<b>7</b> (AZD2716)
a novel, potent secreted phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) inhibitor with excellent preclinical pharmacokinetic properties
across species, clear <i>in vivo</i> efficacy, and minimized
safety risk. Based on accumulated profiling data, (<i>R</i>)-<b>7</b> was selected as a clinical candidate for the treatment
of coronary artery disease
Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a ProteināProtein Interaction
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 proteināprotein
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 Ī¼M, no
detectable activity against GABAa, and with DMPK properties leading
to a predicted dose of 340 mg twice a day oral dosing in humans