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Chemical & Pharmaceutical Bulletin 2022The atropisomeric properties of N-alkyl and N-aryl 4-substituted 5H-dibenz[b,f]azepines were investigated. The N-alkylation and N-arylation of 4-Cl or 4-Me substituted...
The atropisomeric properties of N-alkyl and N-aryl 4-substituted 5H-dibenz[b,f]azepines were investigated. The N-alkylation and N-arylation of 4-Cl or 4-Me substituted compounds was performed; however, none of the atropisomers produced were separated by chiral HPLC. Notably, we observed that the rotation of the four axes (ax. 1-4) in the 4-substituted 5H-dibenz[b,f]azepine structure is so rapid that N-alkylation or N-arylation is not sufficient to freeze it at room temperature. Additionally, the X-ray crystal structures of N-aryl compounds 13b and 14a indicated that the N atom in the triphenyl amine moiety in their structures shows sp-like property.
Topics: Azepines
PubMed: 35908923
DOI: 10.1248/cpb.c22-00265 -
Current Drug Metabolism 2021MIDD0301 is an oral asthma drug candidate that binds GABAA receptors on airway smooth muscle and immune cells. (Comparative Study)
Comparative Study
BACKGROUND
MIDD0301 is an oral asthma drug candidate that binds GABAA receptors on airway smooth muscle and immune cells.
OBJECTIVE
The objective of this study is to identify and quantify MIDD0301 metabolites in vitro and in vivo and determine the pharmacokinetics of oral, IP, and IV administered MIDD0301.
METHODS
In vitro conversion of MIDD0301 was performed using liver and kidney microsomes/S9 fractions followed by quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A LC-MS/MS method was developed using synthesized standards to quantify MIDD0301 and its metabolites in urine and feces. Blood, lung, and brain were harvested from animals that received MIDD0301 by oral, IP, and IV administration, followed by LCMS/ MS quantification. Imaging mass spectrometry was used to demonstrate the presence of MIDD0301 in the lung after oral administration.
RESULTS
MIDD0301 is stable in the presence of liver and kidney microsomes and S9 fractions for at least two hours. MIDD0301 undergoes conversion to the corresponding glucuronide and glucoside in the presence of conjugating cofactors. For IP and IV administration, unconjugated MIDD0301 together with significant amounts of MIDD0301 glucoside and MIDD0301 taurine were found in urine and feces. Less conjugation was observed following oral administration, with MIDD0301 glucuronide being the main metabolite. Pharmacokinetic quantification of MIDD0301 in blood, lung, and brain showed very low levels of MIDD0301 in the brain after oral, IV, or IP administration. The drug half-life in these tissues ranged between 4-6 hours for IP and oral and 1-2 hours for IV administration. Imaging mass spectrometry demonstrated that orally administered MIDD0301 distributes uniformly in the lung parenchyma.
CONCLUSION
MIDD0301 undergoes no phase I and moderate phase II metabolism.
Topics: Administration, Intravenous; Administration, Oral; Animals; Anti-Asthmatic Agents; Azepines; Chromatography, Liquid; Dogs; Female; Humans; Imidazoles; Injections, Intraperitoneal; Kidney; Lung; Mice; Microsomes; Microsomes, Liver; Rats; Tandem Mass Spectrometry; Tissue Distribution
PubMed: 34856893
DOI: 10.2174/1389200222666211202093841 -
Proceedings of the National Academy of... Sep 2022Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To...
Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To understand the physiological impact of CSN function on the CRL network and cell proliferation, we combined quantitative mass spectrometry and genome-wide CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens to identify factors that modulate cell viability upon inhibition of CSN by the small molecule CSN5i-3. CRL components and regulators strongly modulated the antiproliferative effects of CSN5i-3, and in addition we found two pathways involved in genome integrity, SCF-APC/C-GMNN and CUL4-SETD8, that contribute substantially to the toxicity of CSN inhibition. Our data highlight the importance of CSN-mediated NEDD8 deconjugation and adaptive exchange of CRL substrate receptors in sustaining CRL function and suggest approaches for leveraging CSN inhibition for the treatment of cancer.
Topics: Azepines; COP9 Signalosome Complex; Cell Survival; Cullin Proteins; DNA Replication; Imidazoles; NEDD8 Protein; Pyrazoles; Ubiquitin-Protein Ligases
PubMed: 36037385
DOI: 10.1073/pnas.2205608119 -
Drug Design, Development and Therapy 2015Suvorexant, approved in late 2014 in the United States and Japan for the treatment of insomnia characterized by difficulty achieving and/or maintaining sleep, is a dual... (Review)
Review
Suvorexant, approved in late 2014 in the United States and Japan for the treatment of insomnia characterized by difficulty achieving and/or maintaining sleep, is a dual orexin receptor antagonist and the first drug in its class to reach the market. Its development followed from the 1998 discovery of orexins (also called hypocretins), excitatory neuropeptides originating from neurons in the hypothalamus involved in regulation of sleep and wake, feeding behavior and energy regulation, motor activity, and reward-seeking behavior. Suvorexant objectively improves sleep, shortening the time to achieve persistent sleep and reducing wake after sleep onset, although at approved doses (≤20 mg) the benefit was subjectively assessed as modest. Its half-life of 12 hours is relatively long for a modern hypnotic; however, at approved doses (≤20 mg) next-day sedation and driving impairment were much less apparent than at higher doses. Suvorexant is metabolized by the hepatic CYP3A system and should be avoided in combination with strong CYP3A inhibitors. Drug levels are higher in women and obese people; hence, dosing should be conservative in obese women. Administration with food delays drug absorption and is not advised. No dose adjustment is needed for advanced age, renal impairment, or mild-to-moderate hepatic impairment. Suvorexant in contraindicated in narcolepsy and has not been studied in children. In alignment with the changes begun in 2013 in the labeling of other hypnotics, the United States Food and Drug Administration advises that the lowest dose effective to treat symptoms be used and that patients be advised of the possibility of next-day impairment in function, including driving. Infrequent but notable side effects included abnormal dreams, sleep paralysis, and suicidal ideation that were dose-related and reported to be mild. Given its mechanism of action, cataplexy and rapid eye movement (REM) sleep behavior disorder could potentially occur in some patients taking this medication.
Topics: Azepines; Humans; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 26648692
DOI: 10.2147/DDDT.S73224 -
Molecules (Basel, Switzerland) Jun 2021Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most...
Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-]pyrrolo[1,2-]pyrimidines, Pyridofuro[3,2-]pyrido[1,2-]pyrimidines and Pyridofuro[3',2':4,5]pyrimido[1,2-]azepines.
BACKGROUND
Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions.
OBJECTIVE
Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity.
METHODS
For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used.
RESULTS
As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of "open field" and "elevated plus maze" (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds , , and . The studied compounds increase the latent time of first immobilization on the model of "forced swimming" (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound bound tightly in the active site of GABA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at -7.95 kcal/mol, while compound showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT receptor.
CONCLUSIONS
Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.
Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Azepines; Disease Models, Animal; Male; Maze Learning; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Pentylenetetrazole; Pyrimidines; RNA-Binding Proteins; Rats; Receptors, GABA-A; Seizures
PubMed: 34205930
DOI: 10.3390/molecules26113320 -
Medicine Jul 2020Delirium is a frequently encountered complication, which is associated with increased mortality. Suvorexant, an approved agent for the treatment of insomnia, is recently... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Delirium is a frequently encountered complication, which is associated with increased mortality. Suvorexant, an approved agent for the treatment of insomnia, is recently suggested to be also effective for prevention of delirium by some authors. However, a consensus has yet to be reached. The goal of this study was to perform a meta-analysis to overall estimate the effectiveness of suvorexant in preventing delirium and its related consequences.
METHODS
Eligible studies were identified by searching online databases of PubMed, EMBASE, and Cochrane Library. The pooled OR was calculated for binary outcomes (e.g., the incidence of delirium, mortality, or adverse events), while standardized mean difference (SMD) were expressed for continuous outcomes (e.g., time to delirium onset, length of stay in hospital and ICU, time on ventilation).
RESULTS
Seven studies which comprised 402 suvorexant treatment patients and 487 patients with control treatment were included in this meta-analysis. Overall, pooled analysis indicated the incidence of delirium could be significantly reduced (OR, 0.30; P < .001) and time to delirium onset was significantly lengthened (SMD, 0.44; P = .006) in patients undergoing suvorexant treatment compared with controls. Suvorexant had no beneficial effects on the secondary outcomes [length of stay in hospital (SMD, -0.65; P = .161) and ICU (SMD, 0.34; P = .297), time on ventilation (SMD, 1.09; P = .318), drug-related adverse events (OR, drug-related adverse events (OR, 1.66; P = .319) and mortality (OR, 2.21; P = .261)]. Subgroup analysis also confirmed the benefit of suvorexant on the development of delirium, which was significant in any subgroup.
CONCLUSION
Suvorexant should be recommended for the prevention of delirium in clinic.
Topics: Azepines; Delirium; Humans; Length of Stay; Mortality; Respiration, Artificial; Sleep Aids, Pharmaceutical; Time Factors; Triazoles
PubMed: 32791676
DOI: 10.1097/MD.0000000000021043 -
Systematic Reviews Nov 2019This review aimed to assess the existing evidence regarding the clinical effectiveness and safety of pharmacological and non-pharmacological interventions in adults with... (Review)
Review
BACKGROUND
This review aimed to assess the existing evidence regarding the clinical effectiveness and safety of pharmacological and non-pharmacological interventions in adults with insomnia and identify where research or policy development is needed.
METHODS
MEDLINE, Embase, PsycINFO, The Cochrane Library, and PubMed were searched from inception until June 14, 2017, along with relevant gray literature sites. Two reviewers independently screened titles/abstracts and full-text articles, and a single reviewer with an independent verifier completed charting, data abstraction, and quality appraisal.
RESULTS
A total of 64 systematic reviews (35 with meta-analysis) were included after screening 5024 titles and abstracts and 525 full-text articles. Eight of the included reviews were rated as high quality using the Assessment of Multiple Systematic Reviews 2 (AMSTAR2) tool, and over half of the included articles (n = 40) were rated as low or critically low quality. Consistent evidence of effectiveness across multiple outcomes based on more than one high- or moderate quality review with meta-analysis was found for zolpidem, suvorexant, doxepin, melatonin, and cognitive behavioral therapy (CBT), and evidence of effectiveness across multiple outcomes based on one high-quality review with meta-analysis was found for temazepam, triazolam, zopiclone, trazodone, and behavioral interventions. These interventions were mostly evaluated in the short term (< 16 weeks), and there was very little harms data available for the pharmacological interventions making it difficult to evaluate their risk-benefit ratio.
CONCLUSIONS
Assuming non-pharmacological interventions are preferable from a safety perspective CBT can be considered an effective first-line therapy for adults with insomnia followed by other behavioral interventions. Short courses of pharmacological interventions can be supplements to CBT or behavioral therapy; however, no evidence regarding the appropriate duration of pharmacological therapy is available from these reviews.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42017072527.
Topics: Antidepressive Agents; Antipsychotic Agents; Azepines; Benzodiazepines; Cognitive Behavioral Therapy; Comparative Effectiveness Research; Humans; Hypnotics and Sedatives; Melatonin; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Systematic Reviews as Topic; Triazoles; Zolpidem
PubMed: 31730011
DOI: 10.1186/s13643-019-1163-9 -
Cell Research Nov 2015BET inhibition has emerged as a promising epigenetic therapy for malignancies in the last five years, but little consensus has developed regarding what may mediate the... (Review)
Review
BET inhibition has emerged as a promising epigenetic therapy for malignancies in the last five years, but little consensus has developed regarding what may mediate the axis between sensitivity and resistance. Two recent papers published in Nature attempt to address this question in acute myeloid leukemia (AML) and independently identify the Wnt signaling pathway as a driver and biomarker of therapeutic resistance.
Topics: Animals; Azepines; Biomarkers, Tumor; Drug Resistance; Mice; Models, Animal; Neoplasms; Triazoles; Wnt Proteins; Wnt Signaling Pathway
PubMed: 26516144
DOI: 10.1038/cr.2015.127 -
Psychopharmacology Bulletin Feb 2022Insomnia affects more than 10% of the population and causes significant discomfort and disability. Suvorexant is an orexin receptor antagonist that specifically targets... (Review)
Review
PURPOSE OF REVIEW
Insomnia affects more than 10% of the population and causes significant discomfort and disability. Suvorexant is an orexin receptor antagonist that specifically targets the wake-sleep cycle. This review summarizes recent and seminal evidence in the biological and physiological evidence of insomnia, the mechanism of action of suvorexant in treating insomnia, and clinical evidence regarding its use.
RECENT FINDINGS
There is no single clear diagnosis for insomnia, and thus prevalence is not entirely clear, but it is estimated to affect 10%-30% of the adult population. Comorbidities include obesity, diabetes, and various psychiatric conditions, and insomnia likely has a contributing role in these conditions. Insomnia, by definition, impacts sleep quality and also wakefulness, including academic success and work efficiency. Insomnia is likely related to genetic susceptibility and a triggering event, leading to hyper-arousal states and functional brain disturbances. This leads to hyperactivity of the hypothalamic-pituitary-adrenal axis, over-secretion of corticotropin-releasing factor, and aberrancy in neurotransmitter release. Though several pharmacological options exist for the treatment of insomnia, there is equivocal data regarding their efficacy or limits to their use due to side effects and contraindications. Suvorexant is a novel dual orexin receptor antagonist, which is shown to improve sleep by reducing arousals. Unlike classical therapeutics, suvorexant does not alter the sleep profile; it prolongs the time spent in each sleep state. Though it may cause some somnolence, it is milder than reported with other drugs.
SUMMARY
Multiple clinical studies support the use of suvorexant in insomnia. In primary insomnia, suvorexant is effective (over placebo), as measured by polysomnography and reported by patients, in both attaining and maintaining sleep. Similar, albeit to a smaller degree, results were found in secondary insomnia. Suvorexant carries two significant advantages over existing therapies; it has a much better safety profile in approved doses, and it preserves natural sleep architecture, thus promoting more restful sleep and recovery. Unfortunately, data exists mostly for suvorexant versus placebo, and head-to-head trials with common hypnotics are needed to assess the true efficacy of suvorexant over the alternatives. And while tolerance is less likely to develop, close monitoring of post-marketing data is required to evaluate for long term adverse events and efficacy.
Topics: Adult; Azepines; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 35342199
DOI: No ID Found -
ACS Combinatorial Science Jul 2020Physicochemical property switching of chemical space is of great importance for optimization of compounds, for example, for biological activity. Cyclization is a key...
Physicochemical property switching of chemical space is of great importance for optimization of compounds, for example, for biological activity. Cyclization is a key method to control 3D and other properties. A two-step approach, which involves a multicomponent reaction followed by cyclization, is reported to achieve the transition from basic moieties to charge neutral cyclic derivatives. A series of multisubstituted oxazolidinones, oxazinanones, and oxazepanones as well as their thio and sulfur derivatives are synthesized from readily available building blocks with mild conditions and high yields. Like a few other methods, MCR and cyclization allow for the collective transformation of a large chemical space into a related one with different properties.
Topics: Cyclization; Molecular Structure; Oxazepines; Oxazines; Oxazolidinones; Sulfhydryl Compounds
PubMed: 32441919
DOI: 10.1021/acscombsci.0c00072