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.
Roth
Anke G
AG
Institut für Chemie, Humboldt Universität zu Berlin, 12489 Berlin, Germany.
Redmer
S
S
Arenz
Christoph
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002241:Carbohydrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002241:Carbohydrates; D004791:Enzyme Inhibitors; D013108:Sphingomyelin Phosphodiesterase