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

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 CRF<INF>1</INF> 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 <BO>2 </BO>(IC<INF>50</INF> = 0.70 nM), were found to be very potent antagonists of CRF<INF>1</INF>. Compound <BO>8w</BO> showed high CRF<INF>1</INF> 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.