Discovery of a new class of glucosylceramide synthase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 22; pp. 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: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.11.2011; Elsevier
• 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; Inflammation; Gaucher disease; Diabetes; Glucosylceramide synthase inhibitor; GCS; Cancer; Endocrinopathy; Nervous system diseases; Enzyme; Transferases; Diabetes mellitus; Glycosyltransferases; Metabolic diseases; Lipids; Malignant tumor; Enzymopathy; Genetic disease; Cerebral disorder; Ceramide glucosyltransferase; Central nervous system disease; Hexosyltransferases; Inhibitor; Lipoidosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.09.037

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.