Development of carbohydrate-derived inhibitors of acid sphingomyelinase

The acid sphingomyelinase is an emerging drug target, especially for inflammatory lung diseases. Presently, there are no directly-acting potent inhibitors available for cell-based studies. The potent inhibitor phosphatidylinositol-3,5-bisphosphate (PtdIns3,5P2) is not only unsuited for cell culture studies, but also does not provide hints for further structural improvements. In the SAR study described here, we replaced the inositolphosphate moiety by a carbohydrate derivative and the phosphatidic acid residue by an alkylsulfone ester. The resulting compound is more active than its parent compound and offers new means for further structural modification.

A carbohydrate-derived analogue of potent and selective acid sphingomyelinase inhibitor phosphatidylinositol-3,5-bisphosphate was synthesized. This compound is more potent and as selective as its parent compound.Figure optionsDownload as PowerPoint slide