Abstract
Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.
MeSH terms
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Administration, Oral
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Animals
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Anti-Anxiety Agents / chemical synthesis
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Anti-Anxiety Agents / pharmacokinetics
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Anti-Anxiety Agents / pharmacology
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Anxiety / psychology
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Behavior, Animal / drug effects
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Binding, Competitive
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Dogs
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Frontal Lobe / drug effects
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Frontal Lobe / metabolism
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Half-Life
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In Vitro Techniques
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Male
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Pyrazines / chemical synthesis*
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Pyrazines / pharmacokinetics
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Pyrazines / pharmacology
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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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Reaction Time / drug effects
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
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Receptors, Corticotropin-Releasing Hormone / metabolism
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Structure-Activity Relationship
Substances
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8-(butylethylamino)-4-(2,6-dimethoxypyridin-3-yl)-6-methyl-3,4-dihydro-1H-pyrido(2,3-b)pyrazin-2-one
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Anti-Anxiety Agents
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Pyrazines
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Pyridines
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Receptors, Corticotropin-Releasing Hormone
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CRF receptor type 1