Design and Synthesis of Tricyclic Corticotropin-Releasing Factor-1 Antagonists

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 CRF1 antagonists were designed, synthesized, and tested for...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2005-09, Vol.48 (18), p.5780-5793
Main Authors: Gross, Raymond S, Guo, Zhiqiang, Dyck, Brian, Coon, Tim, Huang, Charles Q, Lowe, Richard F, Marinkovic, Dragan, Moorjani, Manisha, Nelson, Jodene, Zamani-Kord, Said, Grigoriadis, Dimitri E, Hoare, Sam R. J, Crowe, Paul D, Bu, Jane Han, Haddach, Mustapha, McCarthy, James, Saunders, John, Sullivan, Robert, Chen, Williams, John P
Format: Article
Language:English
Subjects:
Acenaphthenes
Adrenocorticotropic Hormone - biosynthesis
Animals
Biological and medical sciences
Cells, Cultured
Corticotropin-Releasing Hormone - metabolism
Cyclic AMP - biosynthesis
Drug Design
Female
Heterocyclic Compounds, 3-Ring - chemical synthesis
Heterocyclic Compounds, 3-Ring - chemistry
Heterocyclic Compounds, 3-Ring - pharmacology
Hormones. Endocrine system
Humans
Medical sciences
Molecular Conformation
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Pituitary Gland, Anterior - cytology
Pyrazoles - chemical synthesis
Pyrazoles - chemistry
Pyrazoles - pharmacology
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 CRF1 antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF1 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 CRF1 antagonist with pIC50 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049085v