title: 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.
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.
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA. carolyn.dzierba@bms.com
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Dzierba
authors.forename: Amy G
authors.initials: AG
authors.lastname: Takvorian
authors.forename: Maria
authors.initials: M
authors.lastname: Rafalski
authors.forename: Padmaja
authors.initials: P
authors.lastname: Kasireddy-Polam
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.forename: Snjezana
authors.initials: S
authors.lastname: Lelas
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.forename: John F
authors.initials: JF
authors.lastname: McElroy
authors.forename: Robert C
authors.initials: RC
authors.lastname: Zaczek
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Taub
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gilligan
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D004285:Dogs; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D066298:In Vitro Techniques; D008297:Male; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
chemical_list: C494348:8-(butylethylamino)-4-(2,6-dimethoxypyridin-3-yl)-6-methyl-3,4-dihydro-1H-pyrido(2,3-b)pyrazin-2-one; D014151:Anti-Anxiety Agents; D011719:Pyrazines; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1