5 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
Representative biological network based on differentially expressed genes of the HC group using MetaCoreâ„¢ network software and the Analyze Network algorithm
Two representative networks are shown: the C/EBPβ c-jun network and the NF-κB network. A legend for the biological networks is provided in Additional data file 7d. Red dots in the right corner of a gene indicate up-regulation and blue dots down-regulation.<p><b>Copyright information:</b></p><p>Taken from "Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: a combined transcriptomics and metabolomics analysis"</p><p>http://genomebiology.com/2007/8/9/R200</p><p>Genome Biology 2007;8(9):R200-R200.</p><p>Published online 24 Sep 2007</p><p>PMCID:PMC2375038.</p><p></p
Venn diagram of significantly differentially expressed genes in the LC and HC groups compared to the Con group
ANOVA < 0.01 and FDR (predicted) <p><b>Copyright information:</b></p><p>Taken from "Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: a combined transcriptomics and metabolomics analysis"</p><p>http://genomebiology.com/2007/8/9/R200</p><p>Genome Biology 2007;8(9):R200-R200.</p><p>Published online 24 Sep 2007</p><p>PMCID:PMC2375038.</p><p></p
Design of Selective sPLA<sub>2</sub>‑X Inhibitor (−)-2-{2-[Carbamoyl-6-(trifluoromethoxy)‑1<i>H</i>‑indol-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 (−)-<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 (−)-<b>17</b> was tested in an ApoE<sup>–/–</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, (−)-<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 Indole‑2 Carboxamides as Selective Secreted Phospholipase A<sub>2</sub> Type X (sPLA<sub>2</sub>‑X) 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