Design, synthesis, and biological evaluation of 1,2,3,7-tetrahydro-6h-purin-6-one and 3,7-dihydro-1h-purine-2,6-dione derivatives as corticotropin-releasing factor(1) receptor antagonists

A growing body of evidence suggests that CRF(1) receptor antagonism offers considerable therapeutic potential in the treatment of diseases resulting from elevated levels of CRF, such as anxiety and depression. A series of novel 1,2,3,7-tetrahydro-6H-purin-6-one and 3,7-dihydro-1H-purine-2,6-dione de...

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Published in:Journal of medicinal chemistry 2004-09, Vol.47 (19), p.4741
Main Authors: Hartz, Richard A, Nanda, Kausik K, Ingalls, Charles L, Ahuja, Vijay T, Molski, Thaddeus F, Zhang, Ge, Wong, Harvey, Peng, Yong, Kelley, Michelle, Lodge, Nicholas J, Zaczek, Robert, Gilligan, Paul J, Trainor, George L
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cyclic AMP - metabolism
Drug Design
Humans
Hydroxylation
Inhibitory Concentration 50
Molecular Structure
Purines - chemical synthesis
Purines - chemistry
Purines - pharmacology
Rats
Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors
Receptors, Corticotropin-Releasing Hormone - metabolism
Structure-Activity Relationship
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Summary:A growing body of evidence suggests that CRF(1) receptor antagonism offers considerable therapeutic potential in the treatment of diseases resulting from elevated levels of CRF, such as anxiety and depression. A series of novel 1,2,3,7-tetrahydro-6H-purin-6-one and 3,7-dihydro-1H-purine-2,6-dione derivatives was synthesized and evaluated as corticotropin releasing factor-1 (CRF(1)) receptor antagonists. Compounds within this series, represented by compound 12d (IC(50) = 5.4 nM), were found to be highly potent CRF(1) receptor antagonists. In addition, compounds 12d and 12j were determined to be selective CRF(1) antagonists. The synthesis, structure-activity relationships and pharmacokinetic properties of compounds within this series is presented.
ISSN:0022-2623
DOI:10.1021/jm049787k