title: High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response.
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 CRF(1) 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 CRF(1) 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 microg 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.
authors.affiliation: Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. ising@mpipsykl.mpg.de
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.forename: Ulrich S
authors.initials: US
authors.lastname: Zimmermann
authors.forename: Heike E
authors.initials: HE
authors.lastname: Künzel
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Susan M
authors.initials: SM
authors.lastname: Learned-Coughlin
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
mesh_terms: D000073:Acenaphthenes / Q000627:therapeutic use; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000627:therapeutic use*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D004644:Emotions / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013315:Stress, Psychological / Q000188:drug therapy*; D013997:Time Factors; D000099052:CRF Receptor, Type 1
chemical_list: D000073:Acenaphthenes; C524544:NBI-34041; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D006854:Hydrocortisone