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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 -
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 -
Sleep Medicine Clinics Jun 2020The scope of this article is to review the effects on sleep of prescription drugs that are commonly prescribed for chronic insomnia in adults. The following groups are... (Review)
Review
The scope of this article is to review the effects on sleep of prescription drugs that are commonly prescribed for chronic insomnia in adults. The following groups are discussed: benzodiazepines and its receptor agonists, the dual orexin receptor antagonist suvorexant, melatonin and its receptor agonists, sedating antidepressants, and antipsychotics. Together with the neurobiologic and pharmacologic properties of these drugs, clinical effects are described, including subjective and objective effects on sleep duration, continuity, and architecture. Medical prescription information is given when available. Recently published American and European guidelines for the treatment of insomnia serve as reference frame.
Topics: Antipsychotic Agents; Azepines; Benzodiazepines; Humans; Melatonin; Orexin Receptor Antagonists; Prescription Drugs; Sleep; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 32386689
DOI: 10.1016/j.jsmc.2020.02.002 -
European Journal of Medicinal Chemistry Aug 2021Hymenialdisine an alkaloid of oroidin class has drawn the attention of researchers owing to its unique structural features and interesting biological properties.... (Review)
Review
Hymenialdisine an alkaloid of oroidin class has drawn the attention of researchers owing to its unique structural features and interesting biological properties. Hymenialdisine exhibited promising inhibitory activity against a number of therapeutically important kinases viz., CDKs, GSK-3β etc., and showed anti-cancer, anti-inflammatory, anti-HIV, neuroprotective, anti-fouling, anti-plasmodium properties. Hymenialdisine and other structurally related oroidin alkaloids such as dibromo-hymenialdisine, stevensine, hymenin, axinohydantoin, spongicidines A-D, latonduines and callyspongisines contain pyrrolo[2,3-c] azepin-8-one core in common. Keeping in view of the interesting structural and therapeutic features of HMD, several structural modifications were carried around the fused-azepinone core which resulted in a number of diverse structural motifs like indolo-azepinones, paullones, aza-paullones, darpones and 5,7-dihydro-6H-benzo[b]pyrimido[4,5-d] azepin-6-one. In this review, an attempt is made to collate and review the structures of diverse hymenialdisine and related fused-azepinones of synthetic/natural origin and their biological properties.
Topics: Animals; Anti-HIV Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Azepines; Humans; Molecular Structure; Neuroprotective Agents; Porifera
PubMed: 33901899
DOI: 10.1016/j.ejmech.2021.113445 -
Annals of Neurology Aug 2023
Topics: Humans; Alzheimer Disease; Azepines; Triazoles; Sleep Initiation and Maintenance Disorders
PubMed: 37370256
DOI: 10.1002/ana.26733 -
Expert Review of Clinical Pharmacology Nov 2014Suvorexant (Belsorma(®)) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III... (Review)
Review
Suvorexant (Belsorma(®)) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III studies, with up to 12 months of treatment in adult and elderly patients, there is little doubt that suvorexant induces and maintains sleep. However, the FDA and sponsor disagreed about effective versus safe doses (November 2012). The FDA considered that 5-15 mg were efficient and probably safe, whereas the sponsors had proposed 15-40 mg. The final approved doses are 5, 10, 15 and 20 mg. The major issues are next-morning somnolence and safety as seen in driving tests, with possible signs of muscle weakness, weird dreams, sleep walking, other nighttime behaviors and suicidal ideation. Despite its limitations, suvorexant's market entry offers a truly novel treatment for insomnia, paving the way for follow-up compounds and opening therapeutic avenues in other disorders for orexin receptor modulating compounds.
Topics: Adult; Aged; Animals; Azepines; Dose-Response Relationship, Drug; Drug Approval; Humans; Hypnotics and Sedatives; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles; United States; United States Food and Drug Administration
PubMed: 25318834
DOI: 10.1586/17512433.2014.966813 -
Australasian Psychiatry : Bulletin of... Dec 2017Suvorexant, a new hypnotic, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance, and is used long-term.... (Review)
Review
OBJECTIVE
Suvorexant, a new hypnotic, is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance, and is used long-term. This paper will briefly review suvorexant.
RESULTS
Orexin is a hypothalamic peptide which promotes wakefulness. By blocking orexin receptors, suvorexant induces sleep. Peaking 2 h after ingestion, it has a half-life of 12 h and is hepatically metabolized mainly by CYP3A. Kinetics are not affected by age but concentrations are higher in females and obese patients. There may be interactions with benzodiazepines, antidepressants and antipsychotics. Suvorexant is available in 15 mg and 20 mg doses at which benefits are moderate: after three months' treatment users fell asleep 6 min faster and slept 16 min longer than those on placebo. Studies with 40 mg showed greater benefits but more side effects: next day somnolence, fatigue, xerostomia and peripheral oedema. Hallucinations, sleep paralysis and somnambulism occur rarely. Tolerance, withdrawal and rebound do not generally occur at recommended doses.
CONCLUSION
Suvorexant has not been trialled against other hypnotics, is expensive and its utility for insomnia in patients with psychiatric disorders is unknown. Currently, use of suvorexant could be considered where more established treatments are inappropriate.
Topics: Azepines; Humans; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 28994603
DOI: 10.1177/1039856217734677 -
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 -
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 -
Drugs Oct 2014Suvorexant (Belsomra(®)), a first-in-class, orally active dual orexin-1 receptor and orexin-2 receptor antagonist, has been developed by Merck for the treatment of... (Review)
Review
Suvorexant (Belsomra(®)), a first-in-class, orally active dual orexin-1 receptor and orexin-2 receptor antagonist, has been developed by Merck for the treatment of insomnia. Variations in the levels of the neuropeptides orexin A and orexin B have been linked to circadian rhythms and wakefulness. Orexin-producing neurons in the lateral hypothalamus regulate wakefulness by signalling through orexin receptors. Blockade of orexin receptors is known to promote sleep. Suvorexant was approved in the US in August 2014 for the treatment of adults with sleep onset and/or sleep maintenance insomnia. The drug is also preregistration in Japan, with approval submissions planned for other countries worldwide for this indication. This article summarizes the milestones in the development of suvorexant leading to this first approval for insomnia.
Topics: Azepines; Drug Approval; Humans; Orexin Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 25227290
DOI: 10.1007/s40265-014-0294-5