Development of carbohydrate-derived inhibitors of acid sphingomyelinase

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...

Full description

Saved in:
Bibliographic Details
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.11.030