Synthesis of non-competitive inhibitors of sphingomyelinases with significant activity.
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.
Yokomatsu
Tsutomu
T
School of Pharmacy, Tokyo University of Pharmacy & Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. yokomatu@ps.toyaku.ac.jp
Murano
Tetsuo
T
Akiyama
Takeshi
T
Koizumi
Junichi
J
Shibuya
Shiroshi
S
Tsuji
Yoshiaki
Y
Soeda
Shinji
S
Shimeno
Hiroshi
H
D000818:Animals; D001407:Bacillus / Q000187:drug effects / Q000201:enzymology; D001667:Binding, Competitive / Q000187:drug effects; D002518:Ceramides / Q000138:chemical synthesis* / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008968:Molecular Conformation; D010743:Phospholipids / Q000138:chemical synthesis* / Q000494:pharmacology*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002518:Ceramides; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010743:Phospholipids; D013108:Sphingomyelin Phosphodiesterase