Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage

One of the great challenges of medicinal chemistry is to create novel, effective, chemotherapeutic agents that show specificity for cancer cells combined with low systemic toxicity. A novel idea is to target the enzymes of the NAD biosynthesis and recycling pathways given that cancer cells display a higher NAD turnover rate than healthy cells. To this end, the compound FK866 (APO866; (E)-N-[4-(1-benzoylpiperidin-4-yl) butyl]-3-(pyridin-3-yl) acrylomide), which blocks nicotinamide phosphoribosyltransferase (NMPRTase) has entered clinical trials as a potential chemotherapeutic agent. Here we report the synthesis of analogues of FK866 synthesized by click chemistry.