1 research outputs found
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