1. ¹Max-Planck-Institute of Psychiatry, Munich, Germany
2. ²Neurocrine Biosciences Inc., San Diego, CA, USA
3. ³GlaxoSmithKline, Research Triangle Park, NC, USA

Correspondence: Dr M Ising, Max-Planck-Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany. Tel: +49 89 30622 430; Fax: +49 89 30622 544; E-mail: ising@mpipsykl.mpg.de; Dr DE Grigoriadis, 12790 El Camino Real, Neurocrine Biosciences Inc., San Diego, CA 92130, USA. Tel: +1 858 617 7671; Fax: +1 858 617 7830; E-mail: dgrigoriadis@neurocrine.com

⁴Current address: Department of Psychiatry and Psychotherapy, Universitätsklinikum Carl Gustav Carus, TU Dresden, Fetscherstrasze Str. 74, 01307 Dresden, Germany.

⁵Current address: Klinikum Ingolstadt, Zentrum für Psychiatrie und Psychotherapie, Krumenauerstr. 25, 85021 Ingolstadt, Germany.

Received 8 August 2006; Revised 28 November 2006; Accepted 13 December 2006; Published online 7 February 2007.

Abstract

There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF₁ antagonist NBI-34041/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague–Dawley rats indicate that NBI-34041 is effective in reducing endocrine responses to pharmacological and behavioral challenge mediated by CRF₁ receptors. These specific properties and its well-documented safety profile enabled a clinical Phase I study with 24 healthy male subjects receiving NBI-34041 (10, 50, or 100 mg) or placebo for 14 days. Regulation of the hypothalamic–pituitary–adrenocortical (HPA) axis was evaluated by intravenous stimulation with 100 g of human CRF. Psychosocial stress response was investigated with the Trier Social Stress Test (TSST). Treatment with NBI-34041 did not impair diurnal adrenocorticotropic hormone (ACTH) and cortisol secretion or CRF evoked ACTH and cortisol responses but attenuated the neuroendocrine response to psychosocial stress. These results suggest that NBI-34041 is safe and does not impair basal regulation of the HPA system but improves resistance against psychosocial stress. NBI-34041 demonstrates that inhibition of the CRF system is a promising target for drug development against depression and anxiety disorders.