Design and synthesis of tricyclic corticotropin-releasing factor-1 antagonists.
J Med Chem
; 48(18): 5780-93, 2005 Sep 08.
Article
in En
| MEDLINE
| ID: mdl-16134945
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrazoles
/
Pyridines
/
Receptors, Corticotropin-Releasing Hormone
/
Heterocyclic Compounds, 3-Ring
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2005
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Estados Unidos