-
Chemistry & Biology Jun 2015BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors...
BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors.
Topics: Acetanilides; Adaptor Proteins, Signal Transducing; Apoptosis; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Heterocyclic Compounds, 3-Ring; Humans; Nuclear Proteins; Peptide Hydrolases; Proto-Oncogene Proteins c-myc; Signal Transduction; Thalidomide; Transcription Factors; Triazoles; Ubiquitin-Protein Ligases
PubMed: 26051217
DOI: 10.1016/j.chembiol.2015.05.009 -
Cell Sep 2011MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective,...
MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.
Topics: Animals; Antineoplastic Agents; Azepines; Benzodiazepines; Cell Line, Tumor; Disease Models, Animal; Drug Discovery; Humans; Mice; Multiple Myeloma; Nuclear Proteins; Protein Structure, Tertiary; Proto-Oncogene Proteins c-myc; Transcriptional Activation; Triazoles
PubMed: 21889194
DOI: 10.1016/j.cell.2011.08.017 -
Science (New York, N.Y.) Jun 2015The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part,...
The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.
Topics: Adaptor Proteins, Signal Transducing; Animals; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Crystallography, X-Ray; Disease Models, Animal; Drug Design; Leukemia, Promyelocytic, Acute; Ligands; Mice; Molecular Targeted Therapy; Nuclear Proteins; Peptide Hydrolases; Phthalimides; Protein Stability; Protein Structure, Tertiary; Proteolysis; Tacrolimus Binding Protein 1A; Thalidomide; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 25999370
DOI: 10.1126/science.aab1433 -
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 -
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 -
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 -
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 -
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 -
Molecules (Basel, Switzerland) Mar 2020Biological systems usually respond differently to enantiomers of a chiral molecule due to the inherent chirality of the active receptor sites of enzymes in nature [...].
Biological systems usually respond differently to enantiomers of a chiral molecule due to the inherent chirality of the active receptor sites of enzymes in nature [...].
Topics: Azepines; Benzyl Alcohols; Butyrates; Catalysis; Chemistry Techniques, Synthetic; Epoxy Compounds; Humans; Hydrocarbons, Fluorinated; Propanols; Ruthenium Compounds; Schiff Bases; Stereoisomerism
PubMed: 32168826
DOI: 10.3390/molecules25061266 -
Neurotherapeutics : the Journal of the... Apr 2010Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor... (Review)
Review
Calcitonin gene-related peptide (CGRP) is expressed throughout the central and peripheral nervous systems, consistent with control of vasodilatation, nociception, motor function, secretion, and olfaction. alphaCGRP is prominently localized in primary spinal afferent C and ADelta fibers of sensory ganglia, and betaCGRP is the main isoform in the enteric nervous system. In the CNS there is a wide distribution of CGRP-containing neurons, with the highest levels occurring in striatum, amygdala, colliculi, and cerebellum. The peripheral projections are involved in neurogenic vasodilatation and inflammation, and central release induces hyperalgesia. CGRP is released from trigeminal nerves in migraine. Trigeminal nerve activation results in antidromic release of CGRP to cause non-endothelium-mediated vasodilatation. At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via the brainstem and midbrain to the thalamus and higher cortical pain regions. Recently developed CGRP receptor antagonists are effective at aborting acute migraine attacks. They may act both centrally and peripherally to attenuate signaling within the trigeminovascular pathway.
Topics: Animals; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Humans; Imidazoles; Migraine Disorders; Neurotransmitter Agents; Piperazines; Quinazolines
PubMed: 20430315
DOI: 10.1016/j.nurt.2010.02.004