1. Synthesis, structure-activity relationships, and in vivo properties of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones as corticotropin-releasing factor-1 receptor antagonists.
- Author
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Dzierba CD, Takvorian AG, Rafalski M, Kasireddy-Polam P, Wong H, Molski TF, Zhang G, Li YW, Lelas S, Peng Y, McElroy JF, Zaczek RC, Taub RA, Combs AP, Gilligan PJ, and Trainor GL
- Subjects
- Administration, Oral, Animals, Anti-Anxiety Agents chemical synthesis, Anti-Anxiety Agents pharmacokinetics, Anti-Anxiety Agents pharmacology, Anxiety psychology, Behavior, Animal drug effects, Binding, Competitive, Dogs, Frontal Lobe drug effects, Frontal Lobe metabolism, Half-Life, In Vitro Techniques, Male, Pyrazines pharmacokinetics, Pyrazines pharmacology, Pyridines pharmacokinetics, Pyridines pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Reaction Time drug effects, Receptors, Corticotropin-Releasing Hormone metabolism, Structure-Activity Relationship, Pyrazines chemical synthesis, Pyridines chemical synthesis, Receptors, Corticotropin-Releasing Hormone antagonists & inhibitors
- 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.
- Published
- 2004
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