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Mini Reviews in Medicinal Chemistry 2016BRD4, an epigenetic regulator that recognizes and binds the acetylated lysine residues in histone, has been reported as a potential therapeutic target for cancers. Since... (Review)
Review
BRD4, an epigenetic regulator that recognizes and binds the acetylated lysine residues in histone, has been reported as a potential therapeutic target for cancers. Since the first BRD4 inhibitor JQ1 developed in 2010, numerous BRD4 inhibitors have been discovered in past five years. In this review, we have systematically summarized a series of BRD4 binding compounds, which are divided into five categories based on the similarity of their chemical structures and respectively referred as JQ1 derivatives, tetrahydroquinoline derivatives, 3,5- dimethylisoxazole derivatives, 2-thiazolidinone derivatives and others. The binding affinities for each class of compounds are also discussed.
Topics: Azepines; Binding Sites; Cell Cycle Proteins; Histones; Humans; Molecular Docking Simulation; Nuclear Proteins; Positive Transcriptional Elongation Factor B; Protein Domains; Small Molecule Libraries; Transcription Factors; Triazoles
PubMed: 27290915
DOI: 10.2174/1389557516666160611014130 -
Annual Review of Pharmacology and... Jan 2017Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABA) receptor potentiation to drive sleep through broad suppression of... (Review)
Review
Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABA receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage-specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.
Topics: Animals; Azepines; Drug Discovery; Humans; Orexin Receptor Antagonists; Orexin Receptors; Protein Structure, Secondary; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 27860547
DOI: 10.1146/annurev-pharmtox-010716-104837 -
European Journal of Medicinal Chemistry Jan 2018A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial...
A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial activities against M. tuberculosis (MTB) H37Rv and SDR-TB in the National Institute of Allergy and Infectious Diseases. Triterpenic A-azepano-28-hydroxy-derivatives were synthesized by the reduction with LiAlH of triterpenic azepanones available from the Beckmann rearrangement of the corresponding C3-oximes. Modification of azepanes at NH-group and atoms С12, C20, C28 and C29 of triterpenic core led to the derivatives with oxo, epoxy, aminopropyl, oximino and acyl substituents. The primary assay of tested triterpenoids against MTB H37Rv demonstrated their MIC values ranged from 3.125 to >200 μM. Ursane type A-azepano-28-cinnamoates were the most active being 2 and 4 times more efficient than the initial 28-hydroxy-derivative. The follow-up testing revealed A-azepano-28-cinnamoyloxybetulin as a leader compound with MIC 2 and MBC 4 μM against MTB H37Rv and MICs 4, 1 and 1 μM against INH, RIF and OFX resistant strains, respectively. Five oleanane and ursane azepanes pronounced better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. This work opens a new direction in the design and synthesis of new antitubercular agents basing on azepanotriterpenoids.
Topics: Antitubercular Agents; Azepines; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Triterpenes
PubMed: 29202408
DOI: 10.1016/j.ejmech.2017.11.035 -
Chemistry, An Asian Journal Jan 2022The azepine- and oxepine-embedded polycyclic aromatic hydrocarbons (PAH) 1-3, as the hexa-peri-hexabenzocoronene (HBC)-based nanographenes (NG) were designed and...
The azepine- and oxepine-embedded polycyclic aromatic hydrocarbons (PAH) 1-3, as the hexa-peri-hexabenzocoronene (HBC)-based nanographenes (NG) were designed and synthesized by Diels-Alder reaction of cyclic alkene with tetrachlorothiophene-S,S-dioxide, followed by Suzuki-Miyaura cross-coupling and Scholl-type cyclodehydrogenation. Due to the strained seven-membered ring and the inherent structural pattern, heteroatom-doped NGs 1-3 show C symmetrical, double saddle-helix hybrid conformation, which represents a new shape for HBC based nanographenes. The calculation studies reveal the low aromaticity of the 8π heterocycles themselves and the heterocycles also decrease the electron delocalization of benzenes surrounding them. Dynamics-based calculation suggests the C symmetry would maintain druing the saddle-inversion process. Meanwhile, we show property perturbation by doping with different heteroatoms.
Topics: Azepines; Cycloaddition Reaction; Electrons; Molecular Conformation; Oxepins
PubMed: 34904381
DOI: 10.1002/asia.202101365 -
Journal of Sleep Research Apr 2019In this review, we outline the role of orexin receptor antagonists in disorders of sleep/wake and other potential neuropsychiatric conditions, with a focus on... (Review)
Review
In this review, we outline the role of orexin receptor antagonists in disorders of sleep/wake and other potential neuropsychiatric conditions, with a focus on suvorexant, which is currently the only approved agent in this class. The efficacy of suvorexant was established in Phase 2-3 trials with treatment durations ranging from 1 to 12 months in patients with insomnia. Suvorexant is effective at improving sleep assessed by patient self-report and by polysomnography, with generally little effect on underlying sleep architecture. The main side-effect is next day somnolence. With the growing realization of the important connections between sleep and other disorders, studies are ongoing to explore this novel mechanism in other disorders such as Alzheimer's disease and depression.
Topics: Azepines; Female; Humans; Male; Neuropsychiatry; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 30338596
DOI: 10.1111/jsr.12782 -
Chemical Biology & Drug Design Jan 2018Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide-based...
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide-based compounds were designed and synthesized for cannabinoid CB and CB receptor interactions. Any of the new synthesized compounds showed high affinity for CB receptor with K values superior to 314 nm, whereas some of them showed moderate affinity for CB receptor with K values inferior to 400 nm. 7-Chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited good affinity for CB receptor (K CB = 81 nm) and the highest CB /CB selectively ratio (>12). Docking studies carried out on such compounds were performed using the hCB X-ray in complex with the close pyrazole analogue AM6538 and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB ligands.
Topics: Azepines; Binding Sites; Half-Life; Humans; Ligands; Molecular Docking Simulation; Morpholines; Protein Binding; Protein Structure, Tertiary; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship
PubMed: 28675787
DOI: 10.1111/cbdd.13069 -
Expert Opinion on Investigational Drugs Dec 2014Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. A greater... (Review)
Review
INTRODUCTION
Peripheral T-cell lymphomas (PTCL) are a diverse group of rare non-Hodgkin lymphomas (NHL) that carry a poor prognosis and are in need of effective therapies. A greater understanding of how these tumours proliferate as well as how best to exploit these processes should lead to more durable tumour regression and better clinical outcomes for patients. New approaches include the histone deacetylase inhibitors, antifolates, fusion proteins, nucleoside analogues and agents targeting the immune system, which are being investigated either as single agents or as a combination.
AREAS COVERED
The authors review the evidence for the orally administered aurora A kinase inhibitor MLN8237 ( alisertib ) in T-cell lymphoma. No significant association between clinical response and AAK expression has been observed but inhibition of this enzyme in a Phase II study has demonstrated tumour regression in 27% of heavily pretreated B- and T-cell NHL, with 50% of PTCL patients responding and 3 of 4 patients achieving durable responses.
EXPERT OPINION
A Phase III trial in relapsed PTCL is recruiting patients comparing MLN8237 against single agent comparators. With regards to the data; the response rate of MLN8237 in refractory NHL is promising. The authors believe that further preclinical work identifying the best combinations to take through into clinical trials is important, particularly as this agent is used in earlier lines of therapy.
Topics: Animals; Antineoplastic Agents; Aurora Kinase A; Azepines; Humans; Lymphoma, T-Cell, Peripheral; Protein Kinase Inhibitors; Pyrimidines
PubMed: 25323772
DOI: 10.1517/13543784.2014.972501 -
Cold Spring Harbor Perspectives in... Dec 2014In cancer, epigenetic proteins are intensely studied targets for therapeutic drug discovery, showing great promise. These proteins include the chromatin-modifying... (Review)
Review
In cancer, epigenetic proteins are intensely studied targets for therapeutic drug discovery, showing great promise. These proteins include the chromatin-modifying enzymes that "write" and "erase" histone posttranslational modifications (PTM), and those that "read" these marks through binding modules. In an effort to find a compound that could disrupt the protein-protein interactions between a PTM and reader, JQ1 has proven to be a first-in-class, drug-like inhibitor of the "bromodomain and extraterminal domain" epigenetic readers (BETs), which recognize histone lysine acetylation marks. JQ1 has facilitated the mechanistic study and therapeutic application in cancer of this kind of epigenetic inhibition. By using this chemical probe, we have discovered that the bromodomain inhibitors (BETi) have compelling activity in preclinical models of multiple myeloma and acute myeloid leukemia. In particular, BETi down-regulates the MYC, IL-7R, and E2F transcriptional programs. We are continuously integrating the transcriptional consequences of BETi with changes in the epigenomic landscapes of cancer cells to elucidate the mechanisms underlying response to BETi using chemical and genetic perturbations.
Topics: Azepines; Cell Cycle Proteins; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Humans; Models, Molecular; Neoplasms; Nuclear Proteins; RNA Processing, Post-Transcriptional; Transcription Factors; Triazoles
PubMed: 25452384
DOI: 10.1101/cshperspect.a018663 -
Chembiochem : a European Journal of... Apr 2018Non-cationic and amphipathic indoloazepinone-constrained (Aia) oligomers have been synthesized as new vectors for intracellular delivery. The conformational preferences...
Non-cationic and amphipathic indoloazepinone-constrained (Aia) oligomers have been synthesized as new vectors for intracellular delivery. The conformational preferences of the [l-Aia-Xxx] oligomers were investigated by circular dichroism (CD) and NMR spectroscopy. Whereas Boc-[l-Aia-Gly] -OBn oligomers 12 and 13 and Boc-[l-Aia-β -h-l-Ala] -OBn oligomers 16 and 17 were totally or partially disordered, Boc-[l-Aia-l-Ala] -OBn (14) induced a typical turn stabilized by C - and C -membered H-bond pseudo-cycles and aromatic interactions. Boc-[l-Aia-l-Ala] -OBn (15) exhibited a unique structure with remarkable T-shaped π-stacking interactions involving the indole rings of the four l-Aia residues forming a dense hydrophobic cluster. All of the proposed FITC-6-Ahx-[l-Aia-Xxx] -NH oligomers 19-23, with the exception of FITC-6-Ahx-[l-Aia-Gly] -NH (18), were internalized by MDA-MB-231 cells with higher efficiency than the positive references penetratin and Arg . In parallel, the compounds of this series were successfully explored in an in vitro blood-brain barrier (BBB) permeation assay. Although no passive diffusion permeability was observed for any of the tested Ac-[l-Aia-Xxx] -NH oligomers in the PAMPA model, Ac-[l-Aia-l-Arg] -NH (26) showed significant permeation in the in vitro cell-based human model of the BBB, suggesting an active mechanism of cell penetration.
Topics: Animals; Azepines; Blood-Brain Barrier; Cattle; Cell Line, Tumor; Cell Membrane; Cell Membrane Permeability; Cell-Penetrating Peptides; Drug Carriers; Humans; Indoles; Molecular Conformation; Peptidomimetics
PubMed: 29377388
DOI: 10.1002/cbic.201700678 -
Journal of Medicinal Chemistry Aug 2018Though many studies have been published about therapeutic potentials of selective 5-HTR ligands, there have been few biased ligands of 5-HTR. The development of potent...
Though many studies have been published about therapeutic potentials of selective 5-HTR ligands, there have been few biased ligands of 5-HTR. The development of potent and selective biased ligands of 5-HTR would be of great help in understanding the relationship between pharmacological effects and G protein/β-arrestin signaling pathways of 5-HTR. In order to identify 5-HTR ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives 1 and 2 with arylpyrazolo moiety or arylisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and β-arrestin signaling pathways, 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4- d]azepine 1g was discovered as the β-arrestin biased ligand of 5-HTR. In an electroencephalogram (EEG) test, 1g increased total non-rapid eye movement (NREM) sleep time and decreased total rapid eye movement (REM) sleep time.
Topics: Animals; Azepines; Drug Stability; Eye Movements; HEK293 Cells; Humans; Ligands; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Molecular Docking Simulation; Phenols; Receptors, Serotonin; Serotonin Antagonists; Signal Transduction; Sleep; Sleep, REM; Structure-Activity Relationship; Sulfonamides; beta-Arrestins
PubMed: 30028132
DOI: 10.1021/acs.jmedchem.8b00642