Design and Synthesis of Tricyclic Corticotropin-Releasing Factor-1 Antagonists
Autor: | Charles Q. Huang, James R. McCarthy, Paul D. Crowe, Raymond S. Gross, John Saunders, Dimitri E. Grigoriadis, Jodene Nelson, Richard Lowe, Brian Dyck, John P. Williams, Dragan Marinkovic, Sam R. J. Hoare, Tim Coon, Robert W. Sullivan, Mustapha Haddach, Said Zamani-Kord, Manisha Moorjani, Zhiqiang Guo, Jane Han Bu, Takung Chen |
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Rok vydání: | 2005 |
Předmět: |
endocrine system
medicine.medical_specialty Corticotropin-Releasing Hormone Pyridines Molecular Conformation Neuropeptide Receptors Corticotropin-Releasing Hormone Rats Sprague-Dawley Radioligand Assay Structure-Activity Relationship Adrenocorticotropic Hormone Pituitary Gland Anterior In vivo Internal medicine Drug Discovery Cyclic AMP medicine Animals Humans Structure–activity relationship Receptor Cells Cultured chemistry.chemical_classification Acenaphthenes Antagonist Stereoisomerism Biological activity In vitro Rats Endocrinology chemistry Drug Design Pyrazoles Molecular Medicine Female Heterocyclic Compounds 3-Ring hormones hormone substitutes and hormone antagonists Tricyclic |
Zdroj: | Journal of Medicinal Chemistry. 48:5780-5793 |
ISSN: | 1520-4804 0022-2623 |
DOI: | 10.1021/jm049085v |
Popis: | Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo. |
Databáze: | OpenAIRE |
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