Discovery of C-imidazole azaheptapyridine FPT inhibitors

The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compo...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (3), p.1134-1136
Main Authors: Zhu, Hugh Y., Cooper, Alan B., Desai, Jagdish, Njoroge, George, Kirschmeier, Paul, Bishop, W. Robert, Strickland, Corey, Hruza, Alan, Doll, Ronald J., Girijavallabhan, Viyyoor M.
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Cell Line, Tumor
Crystallography, X-Ray
Drug Discovery - methods
Farnesyltranstransferase - antagonists & inhibitors
Farnesyltranstransferase - metabolism
FPT inhibitors
General aspects
Humans
Imidazoles - chemistry
Imidazoles - metabolism
Imidazoles - pharmacology
Medical sciences
Pharmacology. Drug treatments
Pyridines - chemistry
Pyridines - metabolism
Pyridines - pharmacology
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Summary:The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom. The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.12.013