Abstract
The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) 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 CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.
MeSH terms
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Administration, Oral
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Adrenocorticotropic Hormone / blood
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Animals
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Blood-Brain Barrier / metabolism
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CHO Cells
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Corticotropin-Releasing Hormone / pharmacology
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Cricetinae
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Cricetulus
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Cyclic AMP / antagonists & inhibitors
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Cyclic AMP / biosynthesis
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Drug Design
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology
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Injections, Intravenous
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Male
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Heterocyclic Compounds, 3-Ring
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Imidazoles
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Pyridines
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Receptors, Corticotropin-Releasing Hormone
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CRF receptor type 1
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Adrenocorticotropic Hormone
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Corticotropin-Releasing Hormone
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Cyclic AMP