Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

We identified a series of structurally novel SCD (Delta9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC(50) value of 50 pM in a HEPG2 S...

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Published in:Bioorganic & medicinal chemistry letters 2009-04, Vol.19 (7), p.2048-2052
Main Authors: Koltun, Dmitry O, Parkhill, Eric Q, Vasilevich, Natalya I, Glushkov, Andrei I, Zilbershtein, Timur M, Ivanov, Alexei V, Cole, Andrew G, Henderson, Ian, Zautke, Nathan A, Brunn, Sandra A, Mollova, Nevena, Leung, Kwan, Chisholm, Jeffrey W, Zablocki, Jeff
Format: Article
Language:English
Subjects:
Animals
Cell Line
Drug Evaluation, Preclinical
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Humans
Inhibitory Concentration 50
Microsomes - metabolism
Pteridines - chemistry
Pteridines - metabolism
Pteridines - pharmacology
Quinoxalines - chemistry
Quinoxalines - pharmacology
Rats
Stearoyl-CoA Desaturase - antagonists & inhibitors
Stearoyl-CoA Desaturase - metabolism
Structure-Activity Relationship
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Summary:We identified a series of structurally novel SCD (Delta9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC(50) value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Delta5 and Delta6 desaturases.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.02.019