AbstractSince the discovery of corticotropin‐releasing factor (CRF), extensive research has attempted to provide novel treatment strategies for diseases related to the malfunctions of the hypothalamic–pituitary–adrenocortical (HPA) system. In depression, cerebrospinal fluid levels of CRF are higher than that in normal individuals. Specifically, increased CRF signaling via the CRF1 receptor is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of compounds have been in various stages of development targeting the postulated overactivity of CRF/CRF1‐receptor signaling. NBI 30775, also known as R121919, is a potent, selective, and functional antagonist of the human CRF1 receptor that was being developed as a potentially novel treatment for anxiety and depression. In pharmacological assays in vitro, NBI 30775 was shown to be a potent functional antagonist at the CRF1 receptor, while having little affinity at the CRF2 receptor subtype. In animal studies, this translated into central CRF1 receptor inhibition determined by ex vivo binding studies. NBI 30775 was able to reduce stress‐induced elevations of plasma ACTH. It also exhibited behavioral effects in several animal models measuring both anxiety and depression, which included elevate plus maze, defense withdrawal, and tail suspension tests. Finally, in an open‐label dose‐escalation Phase 2a clinical study in patients with major depressive disorder, NBI 30775 was able to reduce the scores on self‐rated or physician‐administered depression scales in the patients. Although there were no untoward effects seen in the Phase 2a study, the clinical development of this compound was discontinued because of a reversible elevation of liver enzyme activity in two healthy volunteers in a parallel Phase I dose‐escalation study. This first clinical experience has certainly had a positive impact in the efforts to find a safe CRF1 receptor antagonist as a novel therapeutic for depression‐ and anxiety‐related disorders. Drug Dev. Res. 65:216–226, 2005. © 2005 Wiley‐Liss, Inc.