High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response.
paper
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- Authors
- Ising, Marcus; Zimmermann, Ulrich S; Künzel, Heike E; Uhr, Manfred; Foster, Alan C; Learned-Coughlin, Susan M; Holsboer, Florian; Grigoriadis, Dimitri E
- Year
- 2007
- Journal
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
- PMID
- 17287823
- DOI
- 10.1038/sj.npp.1301328
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.
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| Considering Sex as a Biological Variable in Basic and Clinical Studies: An Endocrine Society Scientific Statement. | Bhargava A et al. | — | 2021 | → |
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| Corticotropin-Releasing Factor (CRF) circuit modulation of cognition and motivation. | Hupalo S et al. | — | 2019 | → |
| Depression as a Neuroendocrine Disorder: Emerging Neuropsychopharmacological Approaches beyond Monoamines. | Chávez-Castillo M et al. | — | 2019 | → |
| Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets. | Herman FJ et al. | — | 2019 | → |
| Role of the PACAP system of the extended amygdala in the acoustic startle response in rats. | Seiglie MP et al. | — | 2019 | → |
| Sex differences in the hypothalamic-pituitary-adrenal axis: An obstacle to antidepressant drug development? | Kokras N et al. | — | 2019 | → |
| Discovery of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as novel class of corticotropin releasing factor 1 receptor antagonists. | Kojima T et al. | — | 2018 | → |
| Similar effect of CRF<sub>1</sub> and CRF<sub>2</sub> receptor in the basolateral or central nuclei of the amygdala on tonic immobility behavior. | Spinieli RL et al. | — | 2018 | → |
| The Corticotropin-Releasing Factor Family: Physiology of the Stress Response. | Deussing JM et al. | — | 2018 | → |
| Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model - are we there yet? | Jesulola E et al. | — | 2018 | → |
| Characterization of CRF<sub>1</sub> receptor antagonists with differential peripheral vs central actions in CRF challenge in rats. | Tanaka M et al. | — | 2017 | → |
| Alterations in the corticotropin-releasing hormone (CRH) neurocircuitry: Insights into post stroke functional impairments. | Barra de la Tremblaye P et al. | — | 2016 | → |
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| Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists. | Mochizuki M et al. | — | 2016 | → |
| Postpartum depression: Etiology, treatment and consequences for maternal care. | Brummelte S et al. | — | 2016 | → |
| Region-specific roles of the corticotropin-releasing factor-urocortin system in stress. | Henckens MJ et al. | — | 2016 | → |
| Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress. | Bangasser DA et al. | — | 2016 | → |
| Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21-Hydroxylase Deficiency. | Turcu AF et al. | — | 2016 | → |
| Cognitive disruptions in stress-related psychiatric disorders: A role for corticotropin releasing factor (CRF). | Bangasser DA et al. | — | 2015 | → |
| Corticotropin releasing hormone and imaging, rethinking the stress axis. | Contoreggi C | — | 2015 | → |
| Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. | Dale E et al. | — | 2015 | → |
| Evidence for the role of corticotropin-releasing factor in major depressive disorder. | Waters RP et al. | — | 2015 | → |
| Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia. | Taché Y et al. | — | 2015 | → |
| Interaction of stress, corticotropin-releasing factor, arginine vasopressin and behaviour. | Beurel E et al. | — | 2014 | → |
| Addiction and corticotropin-releasing hormone type 1 receptor antagonist medications. | Contoreggi C et al. | — | 2013 | → |
| Biocatalytic synthesis of chiral alcohols and amino acids for development of pharmaceuticals. | Patel RN | — | 2013 | → |
| Corticotropin-releasing factor 1 receptor antagonists: a patent review. | Williams JP | — | 2013 | → |
| Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm. | Fernández Macedo GV et al. | — | 2013 | → |
| Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring. | Zaidan H et al. | — | 2013 | → |
| The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats. | Million M et al. | — | 2013 | → |
| Design, synthesis, and structure-activity relationships of novel pyrazolo[5,1-b]thiazole derivatives as potent and orally active corticotropin-releasing factor 1 receptor antagonists. | Takahashi Y et al. | — | 2012 | → |
| Effects of corticotropin-releasing factor 1 receptor antagonism on the hypothalamic-pituitary-adrenal axis of rodents. | Gehlert DR et al. | — | 2012 | → |
| Increases of CRF in the amygdala are responsible for reinstatement of methamphetamine-seeking behavior induced by footshock. | Nawata Y et al. | — | 2012 | → |
| Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning? | Griebel G et al. | — | 2012 | → |
| Predicting biological activity: computational approach using novel distance based molecular descriptors. | Dutt R et al. | — | 2012 | → |
| Synthesis and structure-activity relationships of pyrazolo[1,5-a]pyridine derivatives: potent and orally active antagonists of corticotropin-releasing factor 1 receptor. | Takahashi Y et al. | — | 2012 | → |
| Corticotropin releasing factor receptor antagonists for major depressive disorder. | Paez-Pereda M et al. | — | 2011 | → |
| CRF and urocortins: a challenging interaction between family members. | Bhargava A | — | 2011 | → |
| Discovery of N-(1-ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): an orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist. | Hodgetts KJ et al. | — | 2011 | → |
| Discovery of pyrrolo[2,3-d]pyrimidin-4-ones as corticotropin-releasing factor 1 receptor antagonists with a carbonyl-based hydrogen bonding acceptor. | Aso K et al. | — | 2011 | → |
| Glucocorticoids as predictors of treatment response in depression. | Horstmann S et al. | — | 2011 | → |
| Molecular signaling and translational significance of the corticotropin releasing factor system. | Ronan PJ et al. | — | 2011 | → |
| Persistent anxiolytic affects after chronic administration of the CRF₁ receptor antagonist R121919 in rats. | Gutman DA et al. | — | 2011 | → |
| Preliminary evidence of anxiolytic effects of the CRF(1) receptor antagonist R317573 in the 7.5% CO(2) proof-of-concept experimental model of human anxiety. | Bailey JE et al. | — | 2011 | → |
| Allosteric antagonist binding sites in class B GPCRs: corticotropin receptor 1. | Bhattacharya S et al. | — | 2010 | → |
| Allosteric ligands for G protein-coupled receptors: a novel strategy with attractive therapeutic opportunities. | De Amici M et al. | — | 2010 | → |
| Combined Pharmacotherapy and Cognitive-Behavioral Therapy for Anxiety Disorders: Medication Effects, Glucocorticoids, and Attenuated Treatment Outcomes. | Otto MW et al. | — | 2010 | → |
| Cortisol response to individualised graded insulin infusions: a reproducible biomarker for CNS compounds inhibiting HPA activation. | Chen CL et al. | — | 2010 | → |
| Deducing corticotropin-releasing hormone receptor type 1 signaling networks from gene expression data by usage of genetic algorithms and graphical Gaussian models. | Trümbach D et al. | — | 2010 | → |
| Developing small molecule nonpeptidergic drugs for the treatment of anxiety disorders: is the challenge still ahead? | Steckler T | — | 2010 | → |
| Discovery of NBI-77860/GSK561679, a potent corticotropin-releasing factor (CRF1) receptor antagonist with improved pharmacokinetic properties. | Tellew JE et al. | — | 2010 | → |
| Dose-dependent effects of the CRF(1) receptor antagonist R317573 on regional brain activity in healthy male subjects. | Schmidt ME et al. | — | 2010 | → |
| Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. | Coric V et al. | — | 2010 | → |
| Progress in corticotropin-releasing factor-1 antagonist development. | Zorrilla EP et al. | — | 2010 | → |
| Single-nucleotide polymorphisms in corticotropin releasing hormone receptor 1 gene (CRHR1) are associated with quantitative trait of event-related potential and alcohol dependence. | Chen AC et al. | — | 2010 | → |
| Stress hormone regulation: biological role and translation into therapy. | Holsboer F et al. | — | 2010 | → |
| Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models. | Kehne JH et al. | — | 2010 | → |
| Amygdaloid pERK1/2 in corticotropin-releasing hormone overexpressing mice under basal and acute stress conditions. | Silberstein S et al. | — | 2009 | → |
| Analgesic actions of corticotropin-releasing factor (CRF) on somatic pain sensitivity: involvement of glucocorticoid and CRF-2 receptors. | Yarushkina NI et al. | — | 2009 | → |
| A role for corticotropin-releasing factor in functional gastrointestinal disorders. | Taché Y et al. | — | 2009 | → |
| A strategy to minimize reactive metabolite formation: discovery of (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino]-5-oxo-4,5-dihydropyrazine-2-carbonitrile as a potent, orally bioavailable corticotropin-releasing factor-1 receptor antagonist. | Hartz RA et al. | — | 2009 | → |
| Cortagine, a CRF1 agonist, induces stresslike alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways. | Larauche M et al. | — | 2009 | → |
| Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal. | Surget A et al. | — | 2009 | → |
| Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications. | Larauche M et al. | — | 2009 | → |
| CRH signaling. Molecular specificity for drug targeting in the CNS. | Refojo D et al. | — | 2009 | → |
| Drugability of extracellular targets: discovery of small molecule drugs targeting allosteric, functional, and subunit-selective sites on GPCRs and ion channels. | Grigoriadis DE et al. | — | 2009 | → |
| Emerging drugs for major depressive disorder. | Kennedy SH et al. | — | 2009 | → |
| Emerging targets for antidepressant therapies. | Rakofsky JJ et al. | — | 2009 | → |
| In vitro intrinsic clearance-based optimization of N3-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists. | Hartz RA et al. | — | 2009 | → |
| Neuroendocrine control of the gut during stress: corticotropin-releasing factor signaling pathways in the spotlight. | Stengel A et al. | — | 2009 | → |
| Neuropeptide and sigma receptors as novel therapeutic targets for the pharmacotherapy of depression. | Paschos KA et al. | — | 2009 | → |
| Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists. | Hartz RA et al. | — | 2009 | → |
| 2-Arylpyrimidines: novel CRF-1 receptor antagonists. | Yoon T et al. | — | 2008 | → |
| Allosteric ligands for the corticotropin releasing factor type 1 receptor modulate conformational states involved in receptor activation. | Hoare SR et al. | — | 2008 | → |
| Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. | Holsboer F et al. | — | 2008 | → |
| Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. | Lu A et al. | — | 2008 | → |
| Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health. | Derijk RH et al. | — | 2008 | → |
| Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. | Surget A et al. | — | 2008 | → |
| Lymphocyte glucocorticoid receptor resistance and depressive symptoms severity: a preliminary report. | Tanke MA et al. | — | 2008 | → |
| Major depression: emerging therapeutics. | Sen S et al. | — | 2008 | → |
| Making a bad thing worse: adverse effects of stress on drug addiction. | Cleck JN et al. | — | 2008 | → |
| Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety. | Nordquist RE et al. | — | 2008 | → |
| MPZP: a novel small molecule corticotropin-releasing factor type 1 receptor (CRF1) antagonist. | Richardson HN et al. | — | 2008 | → |
| Neurotrophin and neuropeptide expression in mouse brain is regulated by knockout of the norepinephrine transporter. | Haenisch B et al. | — | 2008 | → |
| Novel targets for antidepressant therapies. | Holtzheimer PE et al. | — | 2008 | → |
| Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. | Ising M et al. | — | 2008 | → |
| Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders. | Sommer WH et al. | — | 2008 | → |