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European Journal of Medicinal Chemistry Dec 2017The search for new lead compounds of simple structure, displaying highest quality anti-tumor potency with new mechanisms of action and least adverse effects is the major... (Review)
Review
The search for new lead compounds of simple structure, displaying highest quality anti-tumor potency with new mechanisms of action and least adverse effects is the major intention of cancer drug discovery now a days. For the time being, indole-fused azepines emerged as a simple class of compounds prolifically designed with strong pharmacological significances in particular of cancer protecting ability. In the recent years from the efforts of our research group, indole-fused heteroazepines, a simple structural class achieved by fusion of indole with oxygen, sulphur and nitrogen containing heteroazepine rings, have known for its superior outcomes in cancer treatment. Surprisingly, the chemistry and biology of these unique families with an amazing role in cancer drug discovery has remained broadly unexplored. This short review is consequently an endeavor to highlight the preliminary ideas over this structural class and to draw the medical attention towards future development of indole-fused azepines and analogues for their promising function in cancer drug discovery.
Topics: Animals; Antineoplastic Agents; Azepines; Chemistry Techniques, Synthetic; Drug Design; Humans; Indoles; Neoplasms; Structure-Activity Relationship
PubMed: 28803677
DOI: 10.1016/j.ejmech.2017.07.042 -
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 -
Bioorganic & Medicinal Chemistry Letters Nov 2018The importance of methyl groups in modulating biological activity, selectivity, solubility, metabolism and pharmacokinetic/pharmacodynamic properties of biologically... (Review)
Review
The importance of methyl groups in modulating biological activity, selectivity, solubility, metabolism and pharmacokinetic/pharmacodynamic properties of biologically active molecules is highlighted. The information compiled from selected beneficial cases, focuses mostly on marketed drugs and clinical candidates, and indicates that the methylation strategy has been successful in drug design.
Topics: Animals; Azepines; Dogs; Drug Design; Humans; Methylation; Molecular Structure; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology; Piperidines; Pyrimidines; Rats; Solubility; Triazoles
PubMed: 30243589
DOI: 10.1016/j.bmcl.2018.09.016 -
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 -
Annals of Neurology Aug 2023
Topics: Humans; Alzheimer Disease; Azepines; Triazoles
PubMed: 37381577
DOI: 10.1002/ana.26728 -
Sleep May 2022Effective pharmacological treatments for sleep disturbance related to trauma with and without co-occurring posttraumatic stress disorder (PTSD) are needed. There is... (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVES
Effective pharmacological treatments for sleep disturbance related to trauma with and without co-occurring posttraumatic stress disorder (PTSD) are needed. There is debate regarding what effects on rapid eye movement sleep (REMS) would be beneficial. Suvorexant is the first dual orexin receptor antagonist (DORA) approved for the treatment of insomnia. In contrast to most psychotropic agents, DORAs can enhance REMS while reducing arousal. We evaluated 6 weeks of suvorexant treatment for trauma-related insomnia in a double-blind, placebo-controlled clinical trial with clinical and polysomnographic evaluation.
METHODS
Participants with insomnia that followed a traumatic event were recruited from the community. Representation of current, past-only, and never having met criteria for PTSD was similar and most participants had experienced trauma-related nightmares. Participants were randomly assigned to receive suvorexant or placebo, initially at 10 mg and increased to 20 mg after 1 week, if tolerated. Polysomnography was obtained for screening, at baseline, and at 2 weeks of treatment.
RESULTS
The thirty-seven evaluable participants had significant improvement of PTSD and insomnia symptoms, however, there were no significant interactions with treatment condition. Medication was well tolerated with only one dropout being related to side effects. Within the suvorexant group increased REM segment duration correlated with concurrent PTSD symptom reduction. Nightmares remitted in all of the participants who received suvorexant and all but one of those receiving placebo.
CONCLUSIONS
A robust placebo response undermined detecting a medication effect. Further evaluation of DORAs for trauma-related insomnia, as well as factors contributing to placebo-response, are warranted.
Topics: Azepines; Double-Blind Method; Humans; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 35554590
DOI: 10.1093/sleep/zsac068 -
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 -
The Alkaloids. Chemistry and Biology 2021The chippiines/dippinines/tronocarpine are a family of biologically and structurally interesting polycyclic tryptamine-derived indole alkaloids isolated from the leaf... (Review)
Review
The chippiines/dippinines/tronocarpine are a family of biologically and structurally interesting polycyclic tryptamine-derived indole alkaloids isolated from the leaf and bark extracts of plants belonging to the Tabernaemontana genus. To date, 14 members of this family have been isolated and characterized. This review discusses the isolation, structure determination, biological activity, and proposed biosynthesis of these metabolites. In addition, synthetic studies on the alkaloids are described including approaches to tronocarpine and dippinine B core intermediates and total syntheses of (+)-dippinine B and (+)-tronocarpine.
Topics: Alkaloids; Azepines; Cell Line, Tumor; Humans; Indole Alkaloids; Magnetic Resonance Spectroscopy; Molecular Structure; Neoplasms; Plant Bark; Plant Extracts; Plant Leaves; Plants; Tabernaemontana
PubMed: 33663753
DOI: 10.1016/bs.alkal.2020.07.001 -
Current Organic Synthesis 2022A variety of diseases have been associated with hyperactivation of protein kinase C (PKC) enzymes such as cancer, diabetes, asthma, cardiovascular and central nervous... (Review)
Review
BACKGROUND
A variety of diseases have been associated with hyperactivation of protein kinase C (PKC) enzymes such as cancer, diabetes, asthma, cardiovascular and central nervous system disorders. There is a dire need to selectively inhibit these enzymes by synthesizing new potent inhibitors. Balanol, a fungal metabolite belonging to the PKC inhibitor family, is especially included in this aspect. Tremendous effort has been put towards the synthesis of balanol by different research groups.
OBJECTIVES
The aim of this review is to provide a detailed description of synthetic approaches adopted for the synthesis of key fragments of balanol (azepane and benzophenone). All the factors that resulted in excellent yield and high enantioselectivity have also been mentioned.
CONCLUSION
It has been shown throughout this review that the synthesis of hexahydroazepine and benzophenone cores of balanol was achieved by employing a variety of important key steps with commercially available starting precursors, which make this total synthesis more valuable. Moreover, this article provides ideas to the synthetic as well as pharmaceutical chemists for the synthesis of (-)-balanol and its analogues.
Topics: Azepines; Enzyme Inhibitors; Hydroxybenzoates; Protein Kinase C; Protein Kinase Inhibitors
PubMed: 34370642
DOI: 10.2174/1570179418666210809131917 -
The Journal of Organic Chemistry Apr 2022Herein, we report a multistep synthesis of polycyclic tetrahydroisoquinolines and tetrahydrobenzo[]azepines starting from Wang resin-immobilized allylglycine. After...
Herein, we report a multistep synthesis of polycyclic tetrahydroisoquinolines and tetrahydrobenzo[]azepines starting from Wang resin-immobilized allylglycine. After sulfonylation with 2/4-nitrobenzenesulfonyl chlorides, Mitsunobu alkylation with various phenylalkynols yielded the corresponding (phenylprop-2-yn-1-yl)-sulfonamides. "Interior" ring-closure enyne metathesis (RCEM) using a Grubbs catalyst second generation (Ru2) yielded functionalized tetrahydroisoquinoline/tetrahydrobenzo[]azepine intermediates. "East-side" [4 + 2] cycloaddition with representative dienophiles was followed by the "west-side" construction of different heterocycles using various electrophiles to finally furnish a set of novel molecular frameworks bearing fused [6 + 6] or [6 + 7] rings. The developed methodology enables the facile parallel synthesis of novel, pharmacologically promising compounds derived from privileged scaffolds.
Topics: Allylglycine; Azepines; Cyclization; Polymers; Tetrahydroisoquinolines
PubMed: 35344355
DOI: 10.1021/acs.joc.2c00039