Synthesis of the First Selective Irreversible Inhibitor of Neutral Sphingomyelinase

The sphingolipid ceramide is a candidate second messenger assumed to be involved in fundamental processes such as growth control, inflammation and apoptosis. Many aspects of ceramide-mediated processes remain to be clarified, including the question of which of the different sphingomyelinases is critical for the stimulus-induced ceramide production. Selective inhibitors of the sphingomyelinases are useful tools for clarifying the biological role of these enzymes and, moreover, appear to be interesting motives for the development of pharmacological agents for an experimental therapy of inflammatory diseases. The full synthesis of N-[2-hydroxy-1-(8-oxo-1-oxa-spiro[2.5]octa-4,6-diene-5-ylcarbamoyl)-ethyl] decanamide (2), the first selective irreversible inhibitor of neutral sphingomyelinase, is described and the relevant analytical data are given. The inhibitor 2 was obtained by a five-step synthesis starting from D-serine.