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Journal of Medicinal Chemistry Jun 2014A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design...
Multiparameter optimization in CNS drug discovery: design of pyrimido[4,5-d]azepines as potent 5-hydroxytryptamine 2C (5-HT₂C) receptor agonists with exquisite functional selectivity over 5-HT₂A and 5-HT₂B receptors.
A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.
Topics: Animals; Azepines; Blood-Brain Barrier; CHO Cells; Central Nervous System Agents; Cricetulus; Dogs; Drug Design; Humans; Madin Darby Canine Kidney Cells; Permeability; Pyrimidines; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Structure-Activity Relationship; Urinary Incontinence, Stress
PubMed: 24878222
DOI: 10.1021/jm5003292 -
Chemical Record (New York, N.Y.) Feb 2020Fluorine-containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes... (Review)
Review
Fluorine-containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N-heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine-containing saturated N-heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine-containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.
Topics: Aldehydes; Aza Compounds; Azepines; Cyclization; Fluorine; Heterocyclic Compounds; Oxidation-Reduction; Stereoisomerism
PubMed: 31250972
DOI: 10.1002/tcr.201900025 -
Chemistry, An Asian Journal Feb 2011
Topics: Azepines; Epoxy Compounds; Salts; Sulfonium Compounds
PubMed: 21254413
DOI: 10.1002/asia.201000817 -
Molecular Diversity Aug 2017Alkyl (Z)-3-((2-(N-((E)-3-methoxy-3-oxoprop-1-en-1-yl)acetamido)phenyl)thio)acrylates are obtained from the reaction between 2-methylbenzothiazole and alkyl propiolates...
A synthesis of functionalized arylthio-acrylates, benzo[b][1,4]thiazines and benzo[4,5]thiazolo[3,2-a]azepines from 2-methylbenzothiazole and acetylenic esters in aqueous media.
Alkyl (Z)-3-((2-(N-((E)-3-methoxy-3-oxoprop-1-en-1-yl)acetamido)phenyl)thio)acrylates are obtained from the reaction between 2-methylbenzothiazole and alkyl propiolates in 70% aqueous alcohol, in moderate yields. When dialkyl acetylenedicarboxylates were used under similar conditions, tetra-alkyl 9,10-dihydrobenzo[4,5]thiazolo[3,2-a]azepine-7,8,9,10-tetracarboxylates, together with dialkyl 4-acetyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-2,3-dicarboxylates were obtained in about 4:1 ratios. The stereochemistry of these products has been confirmed by X-ray diffraction.
Topics: Alcohols; Alkynes; Azepines; Benzothiazoles; Crystallography, X-Ray; Esters; Molecular Structure; Stereoisomerism; Thiazines
PubMed: 28639072
DOI: 10.1007/s11030-017-9751-x -
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 -
Bioorganic & Medicinal Chemistry Letters Dec 2010Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of...
Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties.
Topics: Animals; Azepines; Drug Discovery; Rats; Structure-Activity Relationship; TRPV Cation Channels
PubMed: 20947352
DOI: 10.1016/j.bmcl.2010.09.023 -
Journal of Photochemistry and... Jan 2018A majority of previously reported methods suffer from insufficient yields as well as more complicated experimental procedures, a smaller amount of isolated yields...
1,3-Di-n-butylimidazolium tribromide [BBim]Br: An efficient recyclable catalyst mediated synthesis of N-substituted azepines and their biological evaluation-interaction study with human serum albumin.
A majority of previously reported methods suffer from insufficient yields as well as more complicated experimental procedures, a smaller amount of isolated yields involving time-consuming and tiresome work-up with the use of metal catalyst and restricted scope of substrates. To overcome these issues, an environmentally benign, ionic liquid endorsed multi-component protocol to N-substituted azepines has been exploited by means of coupling aromatic amines, dimethyl/diethyl acetylene dicarboxylate, 2,5-dimethoxytetrahydrofuran using 1,3-Di-n-butylimidazolium tribromide [BBim]Br. The catalyst can be recycled and reused for subsequent reactions. The reactivated ionic liquid could be further reused twice as an accelerator All the synthesized compounds were further screened for their antimicrobial properties against three gram positive, four gram negative, and five fungal strains with chloromycin, norflaxacin, and fluconazole as reference drugs. Most of the tested compounds presented significant potency, especially, compound 4e displayed significant antibacterial activity (MIC=1-16μg/mL) whereas compound 4k showed momentous antifungal efficacy (MIC=2-32μg/mL). In addition binding behavior of compound 4e was investigated by binding study between calf thymus DNA and compound 4e by UV-Visible absorption spectroscopy and further research about HSA interactions were carried out. The observed wavelength showed a constancy thus revealing the occurrence of non-covalent π-π stacking interactions of compound 4e and HSA.
Topics: Aniline Compounds; Animals; Anti-Bacterial Agents; Antifungal Agents; Azepines; Catalysis; Cattle; Chemistry Techniques, Synthetic; DNA; Humans; Hydrocarbons, Brominated; Protein Binding; Serum Albumin, Human
PubMed: 29128705
DOI: 10.1016/j.jphotobiol.2017.10.028 -
European Journal of Medicinal Chemistry Dec 2021Dysfunction of the bromo and extra terminal domain (BET) family proteins is associated with many human diseases, therefore the BET family proteins have been considered... (Review)
Review
Dysfunction of the bromo and extra terminal domain (BET) family proteins is associated with many human diseases, therefore the BET family proteins have been considered as promising targets for drug development. Numerous small molecular compounds targeting the N-terminal two tandem bromodomains BD1 and BD2 of the BET family proteins have been reported, and a number of them have been advanced into clinical trials. Most of the BET inhibitors entered clinical trials are pan-BET inhibitors which show poor selectivity among BET members and bind to the BD1 and BD2 of the BET family proteins with comparable binding affinities. In order to elucidate the distinct functions of BD1s and BD2s, many BD1 and BD2 selective BET inhibitors have also been developed. In this review, we summarized the recent progress in the development of BD1 and BD2 selective BET inhibitors, and provided the perspectives for future studies of BET inhibitors.
Topics: Azepines; Drug Development; Humans; Molecular Structure; Protein Domains; Proteins; Triazoles
PubMed: 34547507
DOI: 10.1016/j.ejmech.2021.113853 -
The Journal of Organic Chemistry Nov 2007Pentacyclic pyrrolo- and pyrido[1,2-a]xanthene[1,9-de]azepines were synthesized in various oxidation states by assembling the azepine ring following two strategies:...
Pentacyclic pyrrolo- and pyrido[1,2-a]xanthene[1,9-de]azepines were synthesized in various oxidation states by assembling the azepine ring following two strategies: 7-endo-trig cyclization of the aryl radical derived from a gamma-methylene lactam and cyclodehydration of aldehydes. Other strategies examined (Heck reaction and intramolecular acylation) did not afford azepines, but six-membered nitrogenated rings.
Topics: Azepines; Cyclization; Molecular Structure; Stereoisomerism
PubMed: 17929978
DOI: 10.1021/jo701568w -
CNS Drug Reviews 2006The 5-HT(2C) receptor subtype has been implicated in a wide variety of conditions including obesity, anxiety, depression, obsessive compulsive disorder, schizophrenia,... (Review)
Review
The 5-HT(2C) receptor subtype has been implicated in a wide variety of conditions including obesity, anxiety, depression, obsessive compulsive disorder, schizophrenia, migraine and erectile dysfunction and as a consequence has received considerable attention as a target for drug discovery. Here we review the pharmacological, pharmacokinetic and toxicological profile of WAY-163909 {(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole}, a novel 5-HT(2C) receptor selective agonist. Consistent with a potential therapeutic utility in obesity, schizophrenia and depression WAY-163909 was found to have robust dose-dependent effects in animal models of obesity, psychotic-like behavior or depression.
Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Azepines; Eating; Humans; Indoles; Serotonin 5-HT2 Receptor Agonists
PubMed: 17227285
DOI: 10.1111/j.1527-3458.2006.00167.x