Biological evaluation of sphingomyelin analogues as inhibitors of sphingomyelinase.
Seeking neutral sphingomyelinase inhibitors, we designed and synthesized hydrolytically stable analogues of sphingomyelin. These novel analogues replace the phosphodiester moiety of sphingomyelin with carbamate and urea moiety, resulting in inhibition of neutral sphingomyelinase. Compound 1 prevented ceramide generation and apoptotic neuronal cell death in a model of ischemia based on organotypic hippocampal slice cultures.
Taguchi
Minoru
M
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan. minoru.taguchi@po.rd.taisho.co.jp
Goda
Ken-ichi
K
Sugimoto
Kikuo
K
Akama
Tomoko
T
Yamamoto
Kyoko
K
Suzuki
Taizo
T
Tomishima
Yasumitsu
Y
Nishiguchi
Mariko
M
Arai
Koshi
K
Takahashi
Kenzo
K
Kobori
Takeo
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology; D002518:Ceramides / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents; D008861:Microsomes / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D009924:Organ Culture Techniques; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*; D013109:Sphingomyelins / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002518:Ceramides; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase