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 Factor1 Receptor Antagonists

A growing body of evidence suggests that CRF1 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 deri...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-09, Vol.47 (19), p.4741-4754
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:
Biological and medical sciences
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
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Summary:A growing body of evidence suggests that CRF1 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 (CRF1) receptor antagonists. Compounds within this series, represented by compound 12d (IC50 = 5.4 nM), were found to be highly potent CRF1 receptor antagonists. In addition, compounds 12d and 12j were determined to be selective CRF1 antagonists. The synthesis, structure−activity relationships and pharmacokinetic properties of compounds within this series is presented.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049787k