Novel Chemical Series of 5-Lipoxygenase-Activating Protein Inhibitors for Treatment of Coronary Artery Disease.

5-Lipoxygenase (5-LO)-activating protein (FLAP) inhibitors have proven to attenuate 5-LO pathway activity and leukotriene production in human clinical trials. However, previous clinical candidates have been discontinued and the link between FLAP inhibition and outcome in inflammatory diseases remains to be established. We here describe a novel series of FLAP inhibitors identified from a screen of 10k compounds and the medicinal chemistry strategies undertaken to progress this series.

Design of Selective sPLA-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1-indol-1-yl]pyridine-2-yl}propanoic Acid.

A lead generation campaign identified indole-based sPLA-X inhibitors with a promising selectivity profile against other sPLA isoforms. Further optimization of sPLA selectivity and metabolic stability resulted in the design of (-)-, a novel, potent, and selective sPLA-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)- was tested in an ApoE murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA-X inhibition on atherosclerosis development.

Discovery of a Series of Indole-2 Carboxamides as Selective Secreted Phospholipase A Type X (sPLA-X) Inhibitors.

In order to assess the potential of sPLA-X as a therapeutic target for atherosclerosis, novel sPLA 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.