Masked Bisphosphonate Inhibitors of Acid Sphingomyelinase: Improved Cell Penetration and Potency.

Inhibitors of acid sphingomyelinase (ASM) with nanomolar in cellulo activity were developed by masking the amino bisphosphonate inhibitor ARC39. ASM is a key enzyme catalyzing the hydrolysis of sphingomyelin to ceramide, which plays a role in various physiological and pathological processes. Inhibitors of ASM have been proposed as potential treatment for disorders such as cancer and metastasis, acute lung injury, sepsis, atherosclerosis, and major depression. Despite the vital interest in ASM as a drug target, potent inhibitors of this enzyme are still urgently needed. The masked ARC39 derivatives developed in this study are 100 times more potent than the parent compound. Their properties such as cell uptake, stability, etc. were thoroughly investigated.