AbstractThe different mammalian sphingomyelinases are involved in cell regulation, apoptosis and inflammatory events. Recent reports suggest pharmacological potential especially for inhibitors of the acid sphingomyelinase. Phosphatidyl inositol‐3,5bisphosphate (PtdIns3,5P2) is the most potent selective acid sphingomyelinase inhibitor known to date. In the present study, we synthesized analogues of PtdIns3,5P2 for initial structure–activity‐relationship (SAR) studies. We identified an inhibitor that is easy to synthesize, that has superior chemical and biophysical properties when compared to PtdIns3,5P2 and that should be stable against virtually all phospholipases. Last but not least, the new inhibitor partially protected cells from dexamethasone‐induced cell death.