Development of carbohydrate-derived inhibitors of acid sphingomyelinase

• Published in: Bioorganic & medicinal chemistry 2010-01, Vol.18 (2), p.939-944
• Main Authors: Roth, Anke G., Redmer, S., Arenz, Christoph
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Carbohydrates - chemical synthesis; Carbohydrates - chemistry; Carbohydrates - pharmacology; Cell Line; Drug Evaluation, Preclinical; Enzyme inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Rats; Respiratory system; SAR studies; Sphingolipids; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - isolation & purification; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.11.030

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. 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.