Biological evaluation of sphingomyelin analogues as inhibitors of sphingomyelinase

Minoru Taguchi; Ken-ichi Goda; Kikuo Sugimoto; Tomoko Akama; Kyoko Yamamoto; Taizo Suzuki; Yasumitsu Tomishima; Mariko Nishiguchi; Koshi Arai; Kenzo Takahashi; Takeo Kobori

doi:10.1016/j.bmcl.2003.08.020

Biological evaluation of sphingomyelin analogues as inhibitors of sphingomyelinase

Bioorg Med Chem Lett. 2003 Nov 3;13(21):3681-4. doi: 10.1016/j.bmcl.2003.08.020.

Authors

Minoru Taguchi¹, Ken-ichi Goda, Kikuo Sugimoto, Tomoko Akama, Kyoko Yamamoto, Taizo Suzuki, Yasumitsu Tomishima, Mariko Nishiguchi, Koshi Arai, Kenzo Takahashi, Takeo Kobori

Affiliation

¹ 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

PMID: 14552757
DOI: 10.1016/j.bmcl.2003.08.020

Abstract

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.

MeSH terms

Animals
Apoptosis / drug effects
Brain Ischemia / pathology
Ceramides / chemical synthesis
Ceramides / pharmacology
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Hippocampus / drug effects
Hippocampus / metabolism
In Situ Nick-End Labeling
Indicators and Reagents
Microsomes / drug effects
Neurons / drug effects
Organ Culture Techniques
Rats
Sphingomyelin Phosphodiesterase / antagonists & inhibitors*
Sphingomyelins / pharmacology*
Structure-Activity Relationship

Substances

Ceramides
Enzyme Inhibitors
Indicators and Reagents
Sphingomyelins
Sphingomyelin Phosphodiesterase