Abstract
A lead generation campaign identified indole-based sPLA(2)-X inhibitors with a promising selectivity profile against other sPLA(2) isoforms. Further optimization of sPLA(2) selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA(2)-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)-17 was tested in an ApoE(-/-) murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA(2)-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)-17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.