Design and Synthesis of Tricyclic Imidazo[4,5-b]pyridin-2-ones as Corticotropin-Releasing Factor-1 Antagonists

The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF1) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-ind...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-08, Vol.48 (16), p.5104-5107
Main Authors: Guo, Zhiqiang, Tellew, John E, Gross, Raymond S, Dyck, Brian, Grey, Jonathan, Haddach, Mustapha, Kiankarimi, Mehrak, Lanier, Marion, Li, Bin-Feng, Luo, Zhiyong, McCarthy, James R, Moorjani, Manisha, Saunders, John, Sullivan, Robert, Zhang, Xiaohu, Zamani-Kord, Said, Grigoriadis, Dimitri E, Crowe, Paul D, Chen, Ta Kung, Williams, John P
Format: Article
Language:English
Subjects:
Administration, Oral
Adrenocorticotropic Hormone - blood
Animals
Biological and medical sciences
Blood-Brain Barrier - metabolism
CHO Cells
Corticotropin-Releasing Hormone - pharmacology
Cricetinae
Cricetulus
Cyclic AMP - antagonists & inhibitors
Cyclic AMP - biosynthesis
Drug Design
Heterocyclic Compounds, 3-Ring - chemical synthesis
Heterocyclic Compounds, 3-Ring - pharmacokinetics
Heterocyclic Compounds, 3-Ring - pharmacology
Hormones. Endocrine system
Humans
Imidazoles - chemical synthesis
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Injections, Intravenous
Male
Medical sciences
Pharmacology. Drug treatments
Pyridines - chemical synthesis
Pyridines - pharmacokinetics
Pyridines - pharmacology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
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Summary:The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF1) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF1 antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050384+