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Endocrine Jan 2020We recently reported that inhibition of BET bromodomain suppresses adipogenesis in vitro. In the present study we aimed to address whether BET bromodomain inhibition can...
PURPOSE
We recently reported that inhibition of BET bromodomain suppresses adipogenesis in vitro. In the present study we aimed to address whether BET bromodomain inhibition can suppress adipogenesis in vivo.
METHODS
Brd4 mice were crossed with B6.Cg-Tg(Fabp4-cre)1Rev/J mice to generate Brd4/Fabp4-cre mice. We used high fat diet (HFD, 45% fat) mice treated with vehicle (DMSO) or JQ1 (intraperitoneal, IP injection, 50 mg/kg/day), respectively, for 6 weeks. Body weight was measured once a week. Dual-energy X-ray absorptiometry was determined and brown adipose tissue was harvested at the end of the experiment.
RESULTS
Partial deletion of Brd4 leads to the lower body weight. JQ1 treatment further confirmed that BET bromodomain inhibition suppresses body weight gain and decreases white adipose depots compared with the control mice. In addition, JQ1 treatment reduces the size of brown adipose tissue and impairs its thermogenesis.
CONCLUSIONS
BET bromodomain inhibition suppresses adipogenesis in the mice.
Topics: Adipogenesis; Animals; Azepines; Mice; Nuclear Proteins; Transcription Factors; Triazoles
PubMed: 31691152
DOI: 10.1007/s12020-019-02115-4 -
Chemical Record (New York, N.Y.) Dec 2018With the bromodomain (BRD) inhibitor JQ1, a remarkable success story of BRD4 as a novel drug target has been set off that yielded many anti-cancer drugs that are now in... (Review)
Review
With the bromodomain (BRD) inhibitor JQ1, a remarkable success story of BRD4 as a novel drug target has been set off that yielded many anti-cancer drugs that are now in clinical trials. But not all of the great prospects of BRDs as drug targets may become true. First evaluations of ongoing clinical trials revealed that treatment with BET-inhibitors can be accompanied with significant toxic side effects and the validation of the therapeutic benefit of BET-inhibitors compared to existing therapies is still pending. New strategies that may overcome possible obstacles in BRD drug discovery include combination therapies with other agents, dual target inhibitors, and proteolysis targeting chimeras (PROTACs). Furthermore, non-BET proteins seem promising drug targets as well. Most recently, BRDs have been identified as putative targets to treat parasitic diseases such as malaria. Milestones in BRD drug discovery are reviewed and promising new developments are evaluated.
Topics: Antineoplastic Agents; Azepines; Cell Cycle Proteins; Drug Discovery; Drug Synergism; Humans; Neoplasms; Nuclear Proteins; Proteins; Transcription Factors; Triazoles; Ubiquitin-Protein Ligases
PubMed: 30289209
DOI: 10.1002/tcr.201800074 -
Angewandte Chemie (International Ed. in... Mar 2020The construction of diverse sp -rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the...
The construction of diverse sp -rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the photocatalytic construction of 2,7-diazabicyclo[3.2.1]octanes (bridged 1,3-diazepanes) via a reductive diversion of the Minisci reaction. The fused tricyclic product is proposed to form via radical addition to the C4 position of 4-substituted quinoline substrates, with subsequent Hantzsch ester-promoted reduction to a dihydropyridine intermediate which undergoes in situ two-electron ring closure to form the bridged diazepane architecture. A wide scope of N-arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all-carbon quaternary centers. Computational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity.
Topics: Azepines; Catalysis; Cyclization; Imines; Molecular Structure; Oxidation-Reduction; Photochemical Processes; Quinolines; Stereoisomerism
PubMed: 31914213
DOI: 10.1002/anie.201914390 -
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 -
ChemMedChem Aug 2017An interesting mitochondrial biomarker is the 18-kDa mitochondrial translocator protein (TSPO). Decades of study have shown that this protein plays an important role in... (Review)
Review
An interesting mitochondrial biomarker is the 18-kDa mitochondrial translocator protein (TSPO). Decades of study have shown that this protein plays an important role in a wide range of cellular functions, including opening of the mitochondrial permeability transition pore as well as programmed cell death and proliferation. Variations in TSPO expression have been correlated to different diseases, from tumors to endocrine and neurological disorders. TSPO has therefore become an appealing target for both early diagnosis and selective mitochondrial drug delivery. The number of structurally different TSPO ligands examined has increased over time, highlighting the scientific community's growing understanding of the roles of TSPO in normal and pathological conditions. However, only few TSPO ligands are characterized by the presence of groups that are potentially derivatizable; therefore only few such ligands are well suited for the preparation of targeted prodrugs or nanocarriers able to deliver therapeutics and/or diagnostic agents to mitochondria. This review provides an overview of the very few examples of drug delivery systems characterized by moieties that target TSPO.
Topics: Amides; Animals; Azepines; Drug Carriers; Humans; Ligands; Mitochondria; Nanoparticles; Prodrugs; Protein Binding; Pyrimidines; Receptors, GABA
PubMed: 28771957
DOI: 10.1002/cmdc.201700322 -
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 -
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 -
Blood Reviews Jul 2017Approximately 900,000 people are affected by some sort of venous thromboembolic (VTE) event every year in the United States. VTE diagnosis used to mean treatment with... (Review)
Review
Approximately 900,000 people are affected by some sort of venous thromboembolic (VTE) event every year in the United States. VTE diagnosis used to mean treatment with medications that required routine lab monitoring for safety and efficacy. Activated factor X (FXa) inhibition has emerged as a convenient pathway for management of VTE and currently three FXa inhibitors are available for anticoagulation management - rivaroxaban, apixaban, and edoxaban. Continued development of medications utilizing this pathway may offer advantages via novel pharmacokinetic or pharmacodynamic properties that may minimize the adverse effects associated with traditional anticoagulant therapy. This review summarizes the available information regarding pharmacokinetic, pharmacodynamic, and early safety and efficacy data for three factor Xa inhibitors being developed - darexaban, betrixaban and nokxaban. The studies reviewed in this article suggests that three newer agents possess the potential for promise based on early phase I and II trials.
Topics: Administration, Oral; Animals; Azepines; Benzamides; Blood Coagulation; Drug Discovery; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism
PubMed: 28185693
DOI: 10.1016/j.blre.2017.02.002 -
Journal of Nuclear Medicine : Official... Jul 2020Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for PET or radioimmunotherapy. The...
Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for PET or radioimmunotherapy. The human hepatocyte growth factor receptor (c-MET) signaling pathway is dysregulated in several malignancies, including gastric cancer, and is an important biomarker in drug discovery. Here, we used a photoradiochemical approach to produce Zr-radiolabeled onartuzumab (a monovalent, antihuman c-MET antibody), starting directly from the fully formulated drug (MetMAb). Simultaneous Zr-radiolabeling and protein conjugation was performed in one-pot reactions containing Zr-oxalate, the photoactive chelate desferrioxamine B (DFO)-aryl azide (DFO-ArN), and MetMAb to give Zr-DFO-azepin-onartuzumab. As a control, Zr-DFO-benzyl Bn-isothiocyanate Bn-NCS-onartuzumab was prepared via a conventional two-step process using prepurified onartuzumab and DFO-Bn-NCS. Radiotracers were purified by using size-exclusion methods and evaluated by radiochromatography. Radiochemical stability was studied in human serum, and immunoreactivity was determined by cellular binding assays using MKN-45 gastric carcinoma cells. PET imaging at multiple time points (0-72 h) was performed on female athymic nude mice bearing subcutaneous MKN-45 xenografts. Biodistribution experiments were performed after the final image was obtained. The tumor specificity of Zr-DFO-azepin-onartuzumab was assessed in vivo by competitive inhibition (blocking) studies. Initial photoradiosynthesis experiments produced Zr-DFO-azepin-onartuzumab in less than 15 min, with an isolated decay-corrected radiochemical yield (RCY) of 24.8%, a radiochemical purity of approximately 90%, and a molar activity of approximately 1.5 MBq nmol Reaction optimization improved the radiochemical conversion of Zr-DFO-azepin-onartuzumab to 56.9% ± 4.1% ( = 3), with isolated RCYs of 41.2% ± 10.6% ( = 3) and radiochemical purity of more than 90%. Conventional methods produced Zr-DFO-Bn-NCS-onartuzumab with an isolated RCY of more than 97%, radiochemical purity of more than 97% and molar activity of approximately 14.0 MBq nmol Both radiotracers were immunoreactive and stable in human serum. PET imaging and biodistribution studies showed high tumor uptake for both radiotracers. By 72 h, tumor and liver uptake (percentage injected dose [%ID]) reached 15.37 ± 5.21 %ID g and 6.56 ± 4.03 %ID g, respectively, for Zr-DFO-azepin-onartuzumab ( = 4) and 21.38 ± 11.57 %ID g and 18.84 ± 6.03 %ID g, respectively, for Zr-DFO-Bn-NCS-onartuzumab ( = 4). Blocking experiments gave a statistically significant reduction in tumor uptake (6.34 ± 0.47 %ID g) of Zr-DFO-azepin-onartuzumab ( = 4). The experiments demonstrated that photoradiosynthesis is a viable alternative approach for producing Zr-radiolabeled antibodies directly in protein formulation buffer, reducing protein aggregation and liver uptake.
Topics: Animals; Antibodies, Monoclonal; Azepines; Cell Line, Tumor; Chemistry Techniques, Synthetic; Deferoxamine; Half-Life; Humans; Light; Mice; Positron-Emission Tomography; Proto-Oncogene Proteins c-met; Radiochemistry; Radioisotopes; Tissue Distribution; Zirconium
PubMed: 31924725
DOI: 10.2967/jnumed.119.237180 -
European Journal of Medicinal Chemistry Jun 2019The present status of antibiotic resistant requires an urgent invention of novel agents that act on clinically unexplored antibacterial targets. The enzyme MraY... (Review)
Review
The present status of antibiotic resistant requires an urgent invention of novel agents that act on clinically unexplored antibacterial targets. The enzyme MraY (phospho-MurNAc-pentapeptide translocase), essential for bacterial cell wall synthesis, fulfils this criterion as it has not been explored as a target in a clinical context. Specifically, the enzyme is involved in the lipid-linked cycle of peptidoglycan biosynthesis and is reportedly targeted by naturally-occurring nucleoside antibiotics. The antimicrobial 'caprazamycin' class of nucleoside antibiotics targets Mycobacterium tuberculosis and clinically relevant Gram-negative bacteria such as Pseudomonas aeruginosa besides various drug resistant strains and is therefore an eligible starting point for the development of novel agents. In this review, we aim to summarise the structure-activity relationships of the natural, semi-synthetic as well as synthetic analogues of nucleoside antibiotic caprazamycins. This review highlights caprazamycins as promising lead structures for development of potent and selective antimicrobial agents that target MraY, the bacterial enzyme involved in the first membrane-dependent step in bacterial peptidoglycan assembly.
Topics: Anti-Bacterial Agents; Azepines; Bacterial Proteins; Biological Products; Dose-Response Relationship, Drug; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Transferases; Transferases (Other Substituted Phosphate Groups); Uridine
PubMed: 30933853
DOI: 10.1016/j.ejmech.2019.01.071