Abstract
A series of short-chain analogues of N-palmitoylsphingosine-1-phosphate, modified by replacement of the phosphate and the long alkenyl side chain with hydrolytically stable difluoromethylene phosphonate and phenyl, respectively, were prepared to study the structure-activity relationship for inhibition of sphingomyelinase. The study revealed that inhibition is highly dependent upon the stereochemistry of the asymmetric centers of the acylamino moiety, and resulted in identification of a non-competitive inhibitor with the same level of inhibitory activity of schyphostatin, the most potent of the few known small molecular inhibitors of sphingomyelinase.
MeSH terms
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Animals
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Bacillus / drug effects
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Bacillus / enzymology
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Binding, Competitive / drug effects
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Ceramides / chemical synthesis*
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Ceramides / pharmacology*
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Dogs
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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In Vitro Techniques
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Indicators and Reagents
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Kinetics
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Magnetic Resonance Spectroscopy
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Microsomes / drug effects
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Microsomes / enzymology
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Molecular Conformation
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Phospholipids / chemical synthesis*
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Phospholipids / pharmacology*
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Sphingomyelin Phosphodiesterase / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Ceramides
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Enzyme Inhibitors
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Indicators and Reagents
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Phospholipids
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Sphingomyelin Phosphodiesterase