4 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
Design of Selective sPLA<sub>2</sub>āX Inhibitor (ā)-2-{2-[Carbamoyl-6-(trifluoromethoxy)ā1<i>H</i>āindol-1-yl]pyridine-2-yl}propanoic Acid
A lead
generation campaign identified indole-based sPLA<sub>2</sub>-X inhibitors
with a promising selectivity profile against other
sPLA<sub>2</sub> isoforms. Further optimization of sPLA<sub>2</sub> selectivity and metabolic stability resulted in the design of (ā)-<b>17</b>, a novel, potent, and selective sPLA<sub>2</sub>-X inhibitor
with an exquisite pharmacokinetic profile characterized by high absorption
and low clearance, and low toxicological risk. Compound (ā)-<b>17</b> was tested in an ApoE<sup>ā/ā</sup> murine
model of atherosclerosis to evaluate the effect of reversible, pharmacological
sPLA<sub>2</sub>-X inhibition on atherosclerosis development. Despite
being well tolerated and achieving adequate systemic exposure of mechanistic
relevance, (ā)-<b>17</b> did not significantly affect
circulating lipid and lipoprotein biomarkers and had no effect on
coronary function or histological markers of atherosclerosis
Discovery of a Series of Indoleā2 Carboxamides as Selective Secreted Phospholipase A<sub>2</sub> Type X (sPLA<sub>2</sub>āX) Inhibitors
In order to assess the potential
of sPLA<sub>2</sub>-X as a therapeutic target for atherosclerosis,
novel sPLA<sub>2</sub> inhibitors with improved type X selectivity
are required. To achieve the objective of identifying such compounds,
we embarked on a lead generation effort that resulted in the identification
of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors
with excellent potential for further optimization