piperidines and orvepitant

Major depression is a frequent psychiatric disease. One- third of the depressive patients remain treatment-resistant; thus, it is urgent to find novel antidepressant drugs.. In major depression, in several brain areas the neural networks involved and the alterations of neurotransmitters and neuropeptides are updated. According to these networks, new pharmacological agents and effective combinations of antidepressant drugs achieving a more efficacious antidepressant treatment are suggested.. In the neural networks, the prefrontal cortex has been included. In this brain area, glutamatergic neurons, which receive an activating potential from D2 dopaminergic neurons, presynaptically inhibit M1 muscarinic cholinergic neurons via NMDA receptors. Medium spiny GABAergic/somatostatin neurons, which receive projections from M1 muscarinic cholinergic neurons, presynaptically inhibit D2 dopaminergic neurons via GABAA/somatostatin1 receptors. The combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist can achive a rapid, long-lasting antidepressant effect.. In preclinical studies, the antidepressant effect of orvepitant, an NK1 receptor antagonist, has been demonstrated: this antagonist reaches a complete blockade of NK1 receptors. In clinical studies, the combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist should be investigated indepth as well as the therapeutic effect of orvepitant. In clinical studies, the antidepressant effect of a triple reuptake inhibitor should be examined and compared to current antidepressant drugs.

Topics: Acetamides; Animals; Antidepressive Agents; Bridged Bicyclo Compounds, Heterocyclic; Depressive Disorder, Major; Humans; Muscarinic Antagonists; Neuropeptides; Neurotransmitter Agents; Piperidines; Receptors, N-Methyl-D-Aspartate

Substance P and the neurokinin-1 (NK-1) receptor are implicated in chronic refractory cough pathophysiology. We assessed the efficacy and safety of orvepitant, a brain-penetrant NK-1 antagonist, in an open-label study in CRC patients with chronic refractory cough.. Thirteen patients with daytime cough frequency >3 to <250 coughs/h took orvepitant 30 mg once daily for 4 weeks. Objective cough frequency was measured over 24 h at baseline and weeks 1, 4, and 8. The primary end point was change from Baseline in daytime cough frequency at week 4. Secondary end points included cough severity visual analog scale (VAS) score, global ratings of change for cough frequency and severity, and Cough-specific Quality of Life Questionnaire score.. All patients completed the study. Mean baseline cough frequency was 71.4/h. A statistically and clinically significant improvement in objective daytime cough frequency was observed at week 4: reduction from baseline of 18.9 (26%) coughs/h (95% CI, 9.6-28.3; P < .001). This effect was apparent at week 1 (reduction from baseline of 27.0 [38%] coughs/h [95% CI, 11.4-42.7; P = .001]) and sustained after drug discontinuation at week 8 (reduction from baseline of 20.4 [29%] coughs/h [95% CI, 3.2-37.5; P = .020]). Statistically significant improvements were seen for severity VAS and quality of life. Orvepitant was safe and well-tolerated.. Orvepitant resulted in a significant and sustained improvement in objective cough frequency, severity VAS, and quality of life; appeared safe; and merits further clinical investigation.. EU Clinical Trials Register; No.: 2014-003947-36; URL: www.clinicaltrialsregister.eu.

Topics: Aged; Antitussive Agents; Bridged Bicyclo Compounds, Heterocyclic; Chronic Disease; Cough; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Pilot Projects; Piperidines; Quality of Life; Respiratory Function Tests; Severity of Illness Index; Surveys and Questionnaires

To evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus.. Randomised, double-blind, placebo-controlled clinical trial.. 15 hospitals in Italy and five hospitals in the UK.. 44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment.. 30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1).. The primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus.. The trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was -2.78 (SD: 2.64) points in the 30 mg group, -3.04 (SD: 3.06) points in the 10 mg group and -3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity.. Orvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible.. EudraCT2013-002763-25.

Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Double-Blind Method; Early Termination of Clinical Trials; Female; Humans; Italy; Male; Middle Aged; Neoplasms; Neurokinin-1 Receptor Antagonists; Piperidines; Pruritus; Severity of Illness Index; United Kingdom

Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [(11)C]GR205171 binding indicated that oral orvepitant doses of 30-60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: -2.41, 95% confidence interval (CI) (-4.50 to -0.31) p=0.0245; 60 mg: -2.86, 95% CI (-4.97 to -0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: -1.67, 95% CI (-3.73 to 0.39) p=0.1122; 60 mg: -0.76, 95% CI (-2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD.

Topics: Adult; Aged; Antidepressive Agents; Bridged Bicyclo Compounds, Heterocyclic; Depressive Disorder, Major; Double-Blind Method; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Piperidines; Positron-Emission Tomography; Radioligand Assay

Data suggest that substance P could play an important role in pruritus, and therefore, blockade of the neurokinin (NK)-1 receptor might be antipruritic. Thus, we explored in the Mongolian gerbil the effect on scratching behaviour, induced by intra-dermal injection of the NK-1 receptor-specific agonist GR73632, of oral administration of the NK-1 receptor antagonist orvepitant. Orvepitant at all doses tested (0.1-10 mg/kg p.o.) produced a profound inhibition of GR73632 (30 nmol i.d.) induced hindlimb scratching; the minimum effective dose of orvepitant in this model was identified as ≤0.1 mg/kg. The data generated supported the proposition that the antipruritic potential of orvepitant should be evaluated in clinical trials.

Topics: Administration, Oral; Animals; Antipruritics; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Dose-Response Relationship, Drug; Gerbillinae; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Pruritus; Substance P

The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Cricetinae; Cricetulus; Dogs; Female; Gerbillinae; Half-Life; Humans; Male; Models, Molecular; Molecular Conformation; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Protein Binding; Rats; Receptors, Neurokinin-1