Discovery of a new class of glucosylceramide synthase inhibitors

A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool com...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (22), p.6773-6777
Main Authors: Koltun, Elena, Richards, Steven, Chan, Vicky, Nachtigall, Jason, Du, Hongwang, Noson, Kevin, Galan, Adam, Aay, Naing, Hanel, Art, Harrison, Amanda, Zhang, Jeff, Won, Kwang-Ai, Tam, Danny, Qian, Fawn, Wang, Tao, Finn, Patricia, Ogilvie, Kathleen, Rosen, Jon, Mohan, Raju, Larson, Christopher, Lamb, Peter, Nuss, John, Kearney, Patrick
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Cancer
chemistry
Diabetes
Drug Discovery
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Gaucher disease
GCS
Glucosylceramide synthase inhibitor
Glucosyltransferases - antagonists & inhibitors
Glucosyltransferases - metabolism
Humans
Inflammation
Medical sciences
Mice
Mice, Inbred C57BL
oral administration
Pharmacology. Drug treatments
Structure-Activity Relationship
tissue distribution
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Summary:A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.09.037