Document Report Card

ID: ALA1138815

Journal: J Med Chem

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.

Authors: 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, Trainor GL.

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.

CiteXplore: 15509177

DOI: 10.1021/jm049737f