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Journal of Clinical Hypertension... Jun 2019
Topics: Azepines; Blood Pressure; Humans; Hypertension; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 30874341
DOI: 10.1111/jch.13519 -
American Family Physician Jun 2016
Topics: Azepines; Education, Medical, Continuing; Humans; Practice Guidelines as Topic; Practice Patterns, Physicians'; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 27304771
DOI: No ID Found -
ACS Chemical Neuroscience Sep 2012Suvorexant is a dual orexin antagonist currently in Phase III clinical trials for the modulation of sleep and is being developed by Merck. Recent Phase III results... (Review)
Review
Suvorexant is a dual orexin antagonist currently in Phase III clinical trials for the modulation of sleep and is being developed by Merck. Recent Phase III results showed that patients taking the drug fell asleep faster and slept longer than those on placebo.
Topics: Animals; Azepines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Humans; Hypnotics and Sedatives; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Sleep Initiation and Maintenance Disorders; Triazoles; gamma-Aminobutyric Acid
PubMed: 23024835
DOI: 10.1021/cn300086a -
Journal of Nuclear Medicine : Official... Dec 2017The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent...
The purpose of this study was to assess safety, biodistribution, and radiation dosimetry in humans for the highly selective σ-1 receptor PET agent F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[]thiazol-2(3H)-one (F-FTC-146). Ten healthy volunteers (5 women, 5 men; age ± SD, 34.3 ± 6.5 y) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/MRI examinations were acquired for up to 3 h after injection (357.2 ± 48.8 MBq). Blood samples were collected, and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions of interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry were estimated. All subjects tolerated the PET/MRI examination well, and no adverse reactions to F-FTC-146 were reported. High accumulation of F-FTC-146 was observed in σ-1 receptor-dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose of F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range, 0.0215-0.0301 mSv/MBq). First-in-human studies with clinical-grade F-FTC-146 were successful. Injection of F-FTC-146 is safe, and absorbed doses are acceptable. The potential of F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.
Topics: Adult; Azepines; Benzothiazoles; Female; Healthy Volunteers; Humans; Isotope Labeling; Magnetic Resonance Imaging; Male; Multimodal Imaging; Radiometry; Radiopharmaceuticals; Receptors, sigma; Tissue Distribution; Whole Body Imaging; Sigma-1 Receptor
PubMed: 28572487
DOI: 10.2967/jnumed.117.192641 -
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 -
Chemistry (Weinheim An Der Bergstrasse,... Jul 2017A set of multivalent polyhydroxylated acetamidoazepanes based on ethylene glycol, glucoside, or cyclodextrin scaffolds was prepared. The compounds were assessed against...
A set of multivalent polyhydroxylated acetamidoazepanes based on ethylene glycol, glucoside, or cyclodextrin scaffolds was prepared. The compounds were assessed against plant, mammalian, and therapeutically relevant hexosaminidases. Multimerization was shown to improve the inhibitory potency with synergy, and to fine tune the selectivity profile between related hexosaminidases.
Topics: Animals; Anti-Bacterial Agents; Azepines; Cyclodextrins; Enzyme Inhibitors; Ethylene Glycol; Glucosides; Hexosaminidases; Imino Sugars; Plants
PubMed: 28548311
DOI: 10.1002/chem.201701756 -
Journal of Translational Medicine Jul 2022Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Efficacy of the bromodomain 4 (BRD4) inhibitor JQ1 has been reported for the...
BACKGROUND
Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Efficacy of the bromodomain 4 (BRD4) inhibitor JQ1 has been reported for the treatment of various human cancers, but its potential impact on EC remains unclear. We therefore aimed to elucidate the function of BRD4 and the effects of JQ1 in EC in vivo and in vitro.
METHODS
The mRNA expression of BRD4 was evaluated using datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). BRD4 protein expression in EC tissues was measured using immunohistochemistry (IHC) assays. The effects of JQ1 on EC were determined by using MTT and colony formation assays, flow cytometry and xenograft mouse models. The underlying mechanism was also examined by western blot and small interfering RNA (siRNA) transfection.
RESULTS
BRD4 was overexpressed in EC tissues, and the level of BRD4 expression was strongly related to poor prognosis. The BRD4-specific inhibitor JQ1 suppressed cell proliferation and colony formation and triggered cell apoptosis, cell cycle arrest, and changes in the expression of proteins in related signaling pathways. Moreover, JQ1 decreased the protein expression of BRD4 and c-Myc, and knockdown of BRD4 or c-Myc reduced the viability of EC cells. Intraperitoneal administration of JQ1 (50 mg/kg) significantly suppressed the tumorigenicity of EC cells in a xenograft mouse model.
CONCLUSION
Our results demonstrate that BRD4 is a potential marker of EC and that the BRD4 inhibitor JQ1 is a promising chemotherapeutic agent for the treatment of EC.
Topics: Animals; Apoptosis; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; Female; Humans; Mice; Nuclear Proteins; Proto-Oncogene Proteins c-myc; RNA, Small Interfering; Transcription Factors; Triazoles
PubMed: 35902869
DOI: 10.1186/s12967-022-03545-x -
Journal of Nanobiotechnology Dec 2021The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one...
BACKGROUND
The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one of the most potent cancer treatment strategies for improving the sensitivity of immunotherapy response.
RESULTS
Here, a composite nanostimulator (CNS) was constructed for the release of second near-infrared (NIR-II) photothermal-mediated immune agents, thereby achieving spatiotemporally controllable photothermal-synergized immunotherapy. CNS nanoparticles comprise thermosensitive liposomes as an outer shell and are internally loaded with a NIR-II photothermal agent, copper sulfide (CuS), toll-like receptor-9 (TLR-9) agonist, cytosine-phospho-guanine oligodeoxynucleotides, and programmed death-ligand 1 (PD-L1) inhibitors (JQ1). Following NIR-II photoirradiation, CuS enabled the rapid elevation of localized temperature, achieving tumor ablation and induction of immunogenic cell death (ICD) as well as disruption of the lipid shell, enabling the precise release of two immune-therapeutical drugs in the tumor region. Combining ICD, TLR-9 stimulation, and inhibited expression of PD-L1 allows the subsequent enhancement of dendritic cell maturation and increases infiltration of cytotoxic T lymphocytes, facilitating regional antitumor immune responses.
CONCLUSION
CNS nanoparticle-mediated photothermal-synergized immunotherapy efficiently suppressed the growth of primary and distant tumors in two mouse models and prevented pulmonary metastasis. This study thus provides a novel sight into photo-controllably safe and efficient immunotherapy.
Topics: Animals; Azepines; B7-H1 Antigen; Cell Line, Tumor; Copper; Dendritic Cells; Humans; Immunogenic Cell Death; Immunotherapy; Indocyanine Green; Infrared Rays; Liposomes; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Phototherapy; Toll-Like Receptor 9; Transplantation, Heterologous; Triazoles
PubMed: 34930269
DOI: 10.1186/s12951-021-01197-5 -
Organic Letters Apr 2020(-)-Aurantioclavine (), which contains a characteristic seven-membered ring fused to an indole ring, belongs to the azepinoindole class of fungal clavine alkaloids. Here...
(-)-Aurantioclavine (), which contains a characteristic seven-membered ring fused to an indole ring, belongs to the azepinoindole class of fungal clavine alkaloids. Here we show that starting from a 4-dimethylallyl-l-tryptophan precursor, a flavin adenine dinucleotide (FAD)-binding oxidase and a catalase-like heme-containing protein are involved in the biosynthesis of . The function of these two enzymes was characterized by heterologous expression, characterization, and deuterium labeling experiments.
Topics: Azepines; Biocatalysis; Ergot Alkaloids; Indoles; Molecular Conformation; Oxidoreductases; Penicillium; Tryptophan
PubMed: 32243182
DOI: 10.1021/acs.orglett.0c01132 -
Journal of Neurochemistry Aug 2021Post-traumatic stress disorder (PTSD) is characterized by depression/anxiety and memory failure, primarily fear memory. According to the reports, neuroinflammation and...
Post-traumatic stress disorder (PTSD) is characterized by depression/anxiety and memory failure, primarily fear memory. According to the reports, neuroinflammation and synaptic plasticity can play a role in the neurophysiological mechanisms underlying PTSD. Bromodomain-containing protein 4 (Brd4) intriguingly affects regulating of inflammatory responses and learning and memory. This study aimed to explore the effect of inhibiting Brd4 on depression/anxiety-like behaviors, spatial and fear memory, and underlying mechanisms in a model of PTSD. Inescapable foot shocks (IFS) with a sound reminder in 6 days were used to induce PTSD-like behaviors which were tested using contextual and cue fear tests, sucrose preference test, open-field test, elevated plus maze test, and Y-maze test. Meanwhile, the Brd4 inhibitor JQ1 was used as an intervention. The results found that IFS induced PTSD-like behaviors and indicated obvious Brd4 expression in microglia of the prefrontal cortex (PFC), hippocampus, and amygdala, pro-inflammatory cytokines over-expression, microglial activation, and nuclear factor-kappa B over-expression in PFC and hippocampus but not in amygdala. Meanwhile, the alterations of immediate early genes (IEGs) were found in PFC, hippocampus, and amygdala. Besides, dendritic spine density was reduced in PFC and hippocampus but was elevated in amygdala of rats with IFS. In addition, treatment with JQ1 significantly reduced freezing time in the contextual and cue fear test, reversed the behavioral impairment, decreased the elevated neuroinflammation, and normalized the alteration in IEGs and dendritic spine densities. The results suggested that Brd4 was involved in IFS-induced PTSD-like behaviors through regulating neuroinflammation, dynamics of IEGs, and synaptic plasticity.
Topics: Animals; Anxiety; Azepines; Brain Chemistry; Cues; Dendritic Spines; Depression; Encephalitis; Fear; Gene Expression Regulation; Genes, Immediate-Early; Male; Memory; Motor Activity; Nuclear Proteins; Rats; Rats, Wistar; Stress Disorders, Post-Traumatic; Transcription Factors; Triazoles
PubMed: 34050937
DOI: 10.1111/jnc.15439