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Drugs of Today (Barcelona, Spain : 1998) Jan 2016Suvorexant is a hypnotic representing the first-in-class of a new group of agents known as dual orexin receptor antagonists. They target cerebral orexin receptors which,... (Review)
Review
Suvorexant is a hypnotic representing the first-in-class of a new group of agents known as dual orexin receptor antagonists. They target cerebral orexin receptors which, when activated, contribute to arousal and wakefulness. Suvorexant was shown to decrease sleep onset times and increase sleep duration, whether assessed objectively by polysomnography or subjectively by sleep diaries in primary insomnia patients. Overall tolerability was good, with somnolence being the commonest adverse event (≤ 7% in 3-month studies). No strong signals for rebound or withdrawal were seen after 1-12 months of treatment and few adverse events suggestive of residual psychomotor or cognitive events have been recorded. Further studies are required in patients with insomnia comorbid with depression and head-to-head studies with established hypnotics such as zolpidem and eszopiclone. Studies augmenting the small number of patients evaluating the initial recommended dose (10 mg) would also be prudent.
Topics: Azepines; Clinical Trials as Topic; Drug Interactions; Humans; Orexin Receptor Antagonists; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 26937493
DOI: 10.1358/dot.2016.52.1.2439940 -
Journal of Natural Products Mar 2017This review focuses entirely on the natural bengamides and selected synthetic analogues that have inspired decades of research. Bengamide A was first reported in 1986... (Review)
Review
This review focuses entirely on the natural bengamides and selected synthetic analogues that have inspired decades of research. Bengamide A was first reported in 1986 from the sponge Jaspis cf. coriacea, and bengamide-containing sponges have been gathered from many biogeographic sites. In 2005, a terrestrial Gram-negative bacterium, Myxococcus virescens, was added as a source for bengamides. Biological activity data using varying bengamide-based scaffolds has enabled fine-tuning of structure-activity relationships. Molecular target finding contributed to the creation of a synthetic "lead" compound, LAF389, that was the subject of a phase I anticancer clinical trial. Despite clinical trial termination, the bengamide compound class is still attracting worldwide attention. Future breakthroughs based on the bengamide scaffold are possible and could build on their nanomolar in vitro and positive in vivo antiproliferative and antiangiogenic properties. Bengamide molecular targets include methionine aminopeptidases (MetAP1 and MetAP2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). A mixed PKS/NRPS biosynthetic gene cluster appears to be responsible for creation of the bengamides. This review highlights that the bengamides have driven inspirational studies and that they will remain relevant for future research, even 30 years after the discovery of the first structures.
Topics: Aminopeptidases; Angiogenesis Inhibitors; Animals; Azepines; Humans; Metalloendopeptidases; Methionyl Aminopeptidases; Molecular Structure; NF-kappa B; Porifera
PubMed: 28185457
DOI: 10.1021/acs.jnatprod.6b00970 -
Future Oncology (London, England) Sep 2015Peripheral T-cell lymphomas are aggressive lymphomas with poor outcomes for which novel treatments are urgently needed. Alisertib (MLN8237) is a second-generation oral... (Review)
Review
Peripheral T-cell lymphomas are aggressive lymphomas with poor outcomes for which novel treatments are urgently needed. Alisertib (MLN8237) is a second-generation oral Aurora A kinase inhibitor. Treatment with alisertib results in an accumulation of cells with abnormal mitotic spindles, leading to decreased proliferation and apoptosis in a range of human tumor cell lines. Alisertib has shown single-agent antitumor activity in animal xenograft models and promising antitumor activity alone or in combination with other agents in patients with solid and hematologic cancers, and T-cell lymphomas in particular. It is currently being tested in randomized controlled Phase III trials in relapsed/refractory peripheral T-cell lymphoma.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azepines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Discovery; Drug Evaluation, Preclinical; Humans; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Treatment Outcome
PubMed: 26344156
DOI: 10.2217/fon.15.154 -
Mini Reviews in Medicinal Chemistry 2021Thiazolo- and thiadiazolo-[3,2-a][1,3]diazepines and their patented derivatives, tested with diverse CNS pharmacological activities, constitute an important class of... (Review)
Review
Thiazolo- and thiadiazolo-[3,2-a][1,3]diazepines and their patented derivatives, tested with diverse CNS pharmacological activities, constitute an important class of compounds for new drug development. Therefore, research efforts were continued to design, synthesize, and evaluate compounds for their ultra-short, short-acting hypnotic, anticonvulsant, and neuromuscular blocking activities. The present review provides a summary of the work accomplished by these heterocycles and their biological evaluation.
Topics: Animals; Anticonvulsants; Azepines; GABA-A Receptor Agonists; Humans; Models, Molecular; Molecular Structure; Neuromuscular Blocking Agents; Receptors, GABA-A; Thiazoles
PubMed: 33390131
DOI: 10.2174/1389557521999201230195733 -
Annual Review of Pharmacology and... 2015γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their... (Review)
Review
γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their involvement in Alzheimer's disease, cancer, and other disorders. A clinical trial with the wide-spectrum γ-secretase inhibitor semagacestat has, however, demonstrated that global inhibition of all γ-secretases causes serious toxicity. Evolving insights suggest that selective inhibition of one of these proteases, or more subtle modulation of γ-secretases by stimulating their carboxypeptidase-like activity but sparing their endopeptidase activity, are potentially highly interesting approaches. The rapidly growing knowledge of regulation, assembly, and specificity of these intriguing protein complexes and the potential advent of high-resolution structural information could dramatically change the perspective on safe and efficacious γ-secretase inhibition in various disorders.
Topics: Alanine; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Azepines; Drug Design; Humans; Molecular Structure; Molecular Targeted Therapy; Protease Inhibitors; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Treatment Failure
PubMed: 25292430
DOI: 10.1146/annurev-pharmtox-010814-124309 -
PloS One 2015We performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials evaluating suvorexant for primary insomnia. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
We performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials evaluating suvorexant for primary insomnia.
METHODS
Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations through June 27, 2015. We performed a systematic review and meta-analysis of suvorexant trial efficacy and safety outcomes. The primary efficacy outcomes were either subjective total sleep time (sTST) or subjective time-to-sleep onset (sTSO) at 1 month. The secondary outcomes were other efficacy outcomes, discontinuation rate, and individual adverse events. The risk ratio, number-needed-to-treat/harm, and weighted mean difference (WMD) and 95% confidence intervals (CI) based on a random effects model were calculated.
RESULTS
The computerized literature database search initially yielded 48 results, from which 37 articles were excluded following a review of titles and abstracts and another eight review articles after full-text review. Thus, we identified 4 trials that included a total of 3,076 patients. Suvorexant was superior to placebo with regard to the two primary efficacy outcomes (sTST: WMD = -20.16, 95% CI = -25.01 to -15.30, 1889 patients, 3 trials, sTSO: WMD = -7.62, 95% CI = -11.03 to -4.21, 1889 patients, 3 trials) and was not different from placebo in trial discontinuations. Suvorexant caused a higher incidence than placebo of at least one side effects, abnormal dreams, somnolence, excessive daytime sleepiness/sedation, fatigue, dry mouth, and rebound insomnia.
CONCLUSIONS
Our analysis of published trial results suggests that suvorexant is effective in treating primary insomnia and is well-tolerated.
Topics: Azepines; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles
PubMed: 26317363
DOI: 10.1371/journal.pone.0136910 -
Molecular Pharmaceutics Apr 2020We describe the effects of pH on the structure and bioavailability of MIDD0301, an oral lead compound for asthma. MIDD0301 interacts with peripheral GABA receptors to...
We describe the effects of pH on the structure and bioavailability of MIDD0301, an oral lead compound for asthma. MIDD0301 interacts with peripheral GABA receptors to reduce lung inflammation and airway smooth muscle constriction. The structure of MIDD0301 combines basic imidazole and carboxylic acid function in the same diazepine scaffold, resulting in high solubility at neutral pH. Furthermore, we demonstrated that MIDD0301 can interconvert between a seven-membered ring structure at neutral pH and an acyclic compound at or below pH 3. Both structures have two stable conformers in solution that can be observed by H NMR at room temperature. Kinetic analysis showed opening and closing of the seven-membered ring of MIDD0301 at gastric and intestinal pH, occurring with different rate constants. However, in vivo studies showed that the interconversion kinetics are fast enough to yield similar MIDD0301 blood and lung concentrations for neutral and acidic formulations. Importantly, acidic and neutral formulations of MIDD0301 exhibit high lung distribution with low concentrations in brain. These findings demonstrate that MIDD0301 interconverts between stable structures at neutral and acidic pH without changes in bioavailability, further supporting its formulation as an oral asthma medication.
Topics: Animals; Asthma; Azepines; Benzodiazepines; Biological Availability; Brain; Carboxylic Acids; Female; Hydrogen-Ion Concentration; Imidazoles; Kinetics; Lung; Mice; Muscle, Smooth; Receptors, GABA-A; Solubility; Stomach
PubMed: 32069056
DOI: 10.1021/acs.molpharmaceut.9b01210 -
International Journal of Clinical... Dec 2014To describe the efficacy and safety of suvorexant for the treatment of insomnia. (Review)
Review
Suvorexant for insomnia: a systematic review of the efficacy and safety profile for this newly approved hypnotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?
OBJECTIVE
To describe the efficacy and safety of suvorexant for the treatment of insomnia.
DATA SOURCES
The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov for the search terms 'suvorexant' and 'MK4305'. Briefing documents from the US Food and Drug Administration Peripheral & Central Nervous System Drugs Advisory Committee and product labelling, provided additional information.
STUDY SELECTION
All available clinical reports of studies were identified.
DATA EXTRACTION
Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information.
DATA SYNTHESIS
Suvorexant (MK4305) is the first orexin receptor antagonist approved for the treatment of insomnia. This approval was based in part on a Phase 3 clinical development programme that included two similarly designed, 3-month, randomised, double-blind, placebo-controlled, parallel-group studies examining suvorexant 40 and 20 mg in non-elderly adults (age < 65 years) and 30 and 15 mg in elderly patients (age ≥ 65 years). Suvorexant was superior to placebo for sleep latency as assessed both objectively by polysomnography and subjectively by patient-estimated sleep latency; suvorexant was also superior to placebo for sleep maintenance, as assessed both objectively by polysomnography and subjectively by patient-estimated total sleep time. NNT vs. placebo for response as measured by a ≥ 6 point improvement on the Insomnia Severity Index at month 3 was 8 (95% CI 6-14) for both the higher and lower dose regimens. The most commonly encountered adverse event (incidence ≥ 5% and at least twice the rate of placebo) as identified in product labelling is somnolence, with NNH values vs. placebo of 13 (95% CI 11-18) for suvorexant 40 and 30 mg, and 28 (95% CI 17-82) for suvorexant 20 and 15 mg. The efficacy and tolerability profile of suvorexant is similar for those < 65 and ≥ 65 years of age. Rebound insomnia and withdrawal effects were not observed when suvorexant was discontinued after 3 months or after 12 months of nightly use. Because of concerns about dose-related, next-day effects, including sedation, the recommended dose range is 10-20 mg.
CONCLUSIONS
Suvorexant appears efficacious and relatively tolerable. Its different mechanism of action and potentially different safety and tolerability profile compared with currently available hypnotics represents a new option for the pharmacological treatment of insomnia.
Topics: Azepines; Drug Administration Schedule; Humans; Hypnotics and Sedatives; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles
PubMed: 25231363
DOI: 10.1111/ijcp.12568 -
Brain Research Feb 2020Alcohol use disorder (AUD) is a complex neuropsychiatric disease state in which currently approved pharmacotherapeutics are of relatively low effect at a population... (Review)
Review
Alcohol use disorder (AUD) is a complex neuropsychiatric disease state in which currently approved pharmacotherapeutics are of relatively low effect at a population level. One reason for this may be that current pharmacotherapeutics focus on the reward pathway in relapse prevention, rather than addressing AUD from a holistic perspective. Importantly, one often overlooked symptom of AUD is sleep disruption. In recent years, an efficient, relatively low risk and economic strategy that has proven successful in other disorders is the repositioning or repurposing of drugs approved for the treatment of other indications. Suvorexant, a dual orexin receptor antagonist, has been licensed for the treatment of insomnia in the USA, Australia and Japan. The orexin system also plays a role in the emotional dysregulation that occurs during withdrawal from alcohol use and in alcohol-seeking behaviours. These two factors prompted the planning of a clinical trial into the use of suvorexant to treat insomnia in alcohol dependent individuals during and 24 weeks post-acute alcohol withdrawal. In this review we outline the comorbid nature of AUD and sleep disruptions. We then highlight the role of the orexin system in both sleep-wake regulation and AUD. Finally, we discuss our plan for a Phase II double blind placebo controlled trial examining the effectiveness of suvorexant for the treatment of comorbid insomnia and AUD.
Topics: Alcoholism; Azepines; Benzodiazepines; Clinical Trials, Phase II as Topic; Comorbidity; Humans; Orexin Receptor Antagonists; Orexin Receptors; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 31837287
DOI: 10.1016/j.brainres.2019.146597 -
Journal of Child and Adolescent... Nov 2017Suvorexant is the first dual orexin receptor antagonist for treating insomnia. This study aimed to evaluate the tolerability, efficacy, and safety of suvorexant on...
OBJECTIVES
Suvorexant is the first dual orexin receptor antagonist for treating insomnia. This study aimed to evaluate the tolerability, efficacy, and safety of suvorexant on insomnia in adolescents.
METHODS
Thirty patients (8 male and 22 female; mean standard deviation age: 15.7 ± 2.4 years; range: 10-20) with insomnia were administered suvorexant. Clinical background, persistence rate, the Clinical Global Impression (CGI), and the Athens Insomnia Scale (AIS) were compared between patients who continued and discontinued suvorexant treatment.
RESULTS
Seventeen patients (56.7%) successfully continued taking suvorexant. Among the 13 patients who did not continue treatment, 5 patients were lost to follow-up. Of the remaining eight who did not continue treatment, four decided to discontinue of their own accord, two decided to discontinue due to lack of effectiveness, and two decided to discontinue due to adverse reaction, namely abnormal dreams. Among patients who completed the study, CGI significantly decreased from 3.6 ± 0.8 to 3.1 ± 0.9 (p = 0.014). The score of sleep quality in AIS was significantly higher among the patients who discontinued suvorexant than those who continued suvorexant (p = 0.02).
CONCLUSION
Our results indicate that suvorexant could be considered a treatment option for adolescents.
Topics: Adolescent; Azepines; Dreams; Female; Humans; Male; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles
PubMed: 28520464
DOI: 10.1089/cap.2016.0206