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In order to assess the potential of sPLA 2 -X as a therapeutic target for atherosclerosis, novel sPLA 2 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., Competing Interests: The authors declare no competing financial interest.

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., Competing Interests: The authors declare no competing financial interest.