Synthesis and evaluation of novel phosphate ester analogs as neutral sphingomyelinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2010-07, Vol.20 (13), p.3868-3871
• Main Authors: Imagawa, Hiroshi, Oda, Masataka, Takemoto, Takayuki, Yamauchi, Rieko, Yoshikawa, Tomomi, Yamamoto, Hirofumi, Nishizawa, Mugio, Takahashi, Hironobu, Hashimoto, Manabu, Yabiku, Kenta, Nagahama, Masahiro, Sakurai, Jun
• Format: Article
• Language: English
• Subjects: 2,2'-Dipyridyl - analogs & derivatives; 2,2'-Dipyridyl - chemical synthesis; 2,2'-Dipyridyl - chemistry; 2,2'-Dipyridyl - pharmacology; Analytical, structural and metabolic biochemistry; Bacillus cereus - enzymology; Biological and medical sciences; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrolases; Hydrolysis; Inhibitor; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; SMase; Sphingomyelin; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelinase; Sphingosine - analogs & derivatives; Sphingosine - chemical synthesis; Sphingosine - chemistry; Sphingosine - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.05.042

A novel sphingomyelin inhibitor RY221B-a, which contains a bipyridyl moiety as a metal coordination site was designed based upon the mechanism of phosphate ester hydrolysis. RY221B-a was synthesized from N-Boc-sphingosine in three steps via selective etherification using stannyl acetal. Synthesized RY221B-a exhibited relatively-strong inhibitory activity against Bc-SMase (IC 50 = 1.2 μM).