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Bioorganic & Medicinal Chemistry Oct 2017Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H receptor. Two series...
Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a K value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; K=25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; K=34nM), classified as antagonists in a cAMP accumulation assay (IC=4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hHR vs hHR>600-fold) and low toxicity (hERG inhibition: IC>1.70µM; hepatotoxicity IC>12.5µM; non-mutagenic up to 10µM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring.
Topics: Animals; Azepines; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; HEK293 Cells; Hep G2 Cells; Humans; Ligands; Male; Molecular Structure; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M3; Receptors, Histamine H1; Receptors, Histamine H3; Structure-Activity Relationship
PubMed: 28797771
DOI: 10.1016/j.bmc.2017.07.058 -
CNS Spectrums Jun 2016Suovrexant is a novel hypnotic and is the only agent clinically available that works by blocking orexin-ergic mechanisms.
Suovrexant is a novel hypnotic and is the only agent clinically available that works by blocking orexin-ergic mechanisms.
Topics: Arousal; Azepines; Humans; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Triazoles; Wakefulness
PubMed: 27322687
DOI: 10.1017/S1092852916000225 -
The Journal of Organic Chemistry Sep 2021A scandium trifluoromethanesulfonate-catalyzed reaction of donor-acceptor cyclopropanes with 6-amino-1,3-dimethyluracil was found to proceed as three-membered ring...
A scandium trifluoromethanesulfonate-catalyzed reaction of donor-acceptor cyclopropanes with 6-amino-1,3-dimethyluracil was found to proceed as three-membered ring opening via nucleophilic attack of the C(5) atom of an ambident nucleophile serving as an enamine equivalent. It was shown that, under basic conditions, the obtained products underwent cyclization to 6,7-dihydro-1-pyrimido[4,5-]azepine-2,4,8-triones, an interesting subclass of nucleobase analogues.
Topics: Azepines; Cyclization; Cyclopropanes; Uracil
PubMed: 34382810
DOI: 10.1021/acs.joc.1c01064 -
Organic Letters May 2022A chiral phosphoric acid-catalyzed thio-Michael addition/enantioselective protonation has been developed for the first time. The reaction applies...
A chiral phosphoric acid-catalyzed thio-Michael addition/enantioselective protonation has been developed for the first time. The reaction applies 7-methylene-6-aryl-7-dibenzo[]azepines, products of Pd-catalyzed imidoylative Heck cyclization, as Michael acceptors in reactions with a wide range of aryl thiols. Diversified 7-[(arylthio)methyl]-7-dibenzo[]azepines bearing a benzylic stereocenter and a thermodynamically regulated biaryl axis were produced with good to excellent enantioselectivity and 14-25:1 diastereoisomeric ratios.
Topics: Azepines; Catalysis; Cyclization; Stereoisomerism
PubMed: 35549333
DOI: 10.1021/acs.orglett.2c01217 -
Neurology Sep 2014
Topics: Azepines; Calcitonin Gene-Related Peptide Receptor Antagonists; Female; Humans; Imidazoles; Male; Migraine Disorders
PubMed: 25107883
DOI: 10.1212/WNL.0000000000000782 -
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 -
Expert Opinion on Drug Discovery 2016The cost to develop a new drug from target discovery to market is a staggering $1.8 billion, largely due to the very high attrition rate of drug candidates and the... (Review)
Review
INTRODUCTION
The cost to develop a new drug from target discovery to market is a staggering $1.8 billion, largely due to the very high attrition rate of drug candidates and the lengthy transition times during development. Open access is an emerging model of open innovation that places no restriction on the use of information and has the potential to accelerate the development of new drugs.
AREAS COVERED
To date, no quantitative assessment has yet taken place to determine the effects and viability of open access on the process of drug translation. This need is addressed within this study. The literature and intellectual property landscapes of the drug candidate JQ1, which was made available on an open access basis when discovered, and conventionally developed equivalents that were not are compared using the Web of Science and Thomson Innovation software, respectively.
EXPERT OPINION
Results demonstrate that openly sharing the JQ1 molecule led to a greater uptake by a wider and more multi-disciplinary research community. A comparative analysis of the patent landscapes for each candidate also found that the broader scientific diaspora of the publically released JQ1 data enhanced innovation, evidenced by a greater number of downstream patents filed in relation to JQ1. The authors' findings counter the notion that open access drug discovery would leak commercial intellectual property. On the contrary, JQ1 serves as a test case to evidence that open access drug discovery can be an economic model that potentially improves efficiency and cost of drug discovery and its subsequent commercialization.
Topics: Access to Information; Azepines; Drug Design; Drug Discovery; Drug Industry; Humans; Intellectual Property; Models, Economic; Molecular Targeted Therapy; Patents as Topic; Time Factors; Triazoles
PubMed: 26791045
DOI: 10.1517/17460441.2016.1144587 -
Phytotherapy Research : PTR Nov 2020Securinine (Sec) is a naturally derived compound separated from the roots of Securinega suffruticosa, which has long been used as a herbal medicine. Sec is widely known...
Securinine (Sec) is a naturally derived compound separated from the roots of Securinega suffruticosa, which has long been used as a herbal medicine. Sec is widely known as a GABA receptor antagonist, it is also known as an innate immune cell agonist and has been reported to increase macrophage activity and promote monocyte maturation. On the basis of these studies, we investigated the effect of Sec on osteoclast differentiation and bone resorbing function. We have found that Sec inhibits RANKL-induced osteoclast differentiation, fusion, actin ring formation, and bone resorbing function by the inhibition of gene expression associated with each stage. Moreover, Sec significantly suppressed osteoclastogenesis by decreasing the phosphorylation of p38, Akt, JNK, IκB, and PLCγ2, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos and NFATc1. Finally, Sec effectively protected bone loss induced by the excessive inflammatory responses and activity of osteoclasts in vivo by a micro-CT and histological analysis. In conclusion, our findings suggest that Sec may be a promising drug for bone metabolic diseases such as osteoporosis, which is associated with the excessive activity of osteoclasts.
Topics: Animals; Azepines; Bone Diseases, Metabolic; Cell Differentiation; Herbal Medicine; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Mice; Osteogenesis; Piperidines
PubMed: 32510717
DOI: 10.1002/ptr.6735 -
European Journal of Medicinal Chemistry 2015Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us,...
Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us, as well as the consideration that heterocycle fused tetrazepinones bearing the 2-chloroethyl substituent show a better cytotoxic profile than temozolomide and mitozolomide against human cancer cell lines which express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), in this paper we report the multistep synthesis and the biological study of 3-(2-chloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 10. Like compound 7, it was active on P-glycoprotein expressing cells (MDR) HL60 and on K562 cell line that are resistant to apoptosis induced by different stimuli, showing GI50 values of 14 and 18 μM respectively. As an antiproliferative agent against the above cells compound 10 was about 2.2 times more active than compound 7. Compound 10 was also tested against WiDR cells which are overexpressing the DNA repair protein MGMT, showing a GI50 value of 2.3 μM. Finally, concerning the effect on cell cycle we observed an evident difference between compounds 7 and 10. In fact, compound 7 induces a block of cell cycle in G0-G1, therefore acting as phase-specific drug, in contrast, compound 10 is a not phase-specific agent. Both the compounds are able to increase the apoptotic sub G0-G1 peak of cell cycle.
Topics: Antineoplastic Agents; Apoptosis; Azepines; Cell Cycle; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; K562 Cells; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 25874335
DOI: 10.1016/j.ejmech.2015.04.004 -
Chemical & Pharmaceutical Bulletin 2019Natural products are still rich sources of clinically used medicines and lead compounds for them. This review summarizes chemical studies carried out by the author on... (Review)
Review
Natural products are still rich sources of clinically used medicines and lead compounds for them. This review summarizes chemical studies carried out by the author on natural products of microorganism origin, many of which were discovered at the Institute of Microbial Chemistry (BIKAKEN). Caprazamycin B is a liponucleoside antibiotic from which CPZEN-45, an antituberculosis agent with a unique mode of action, was developed. Intervenolin and leucinostatin A exert antiproliferative activity toward tumor cells in the presence of the corresponding stromal cells, which implies that the primary molecular targets of these molecules should be related to growth signals from normal (stromal) cells. Details of the endeavors to establish efficient synthetic routes to these compounds which accelerated structure-activity relationship studies and further evaluation of biological activity are described.
Topics: Anti-Infective Agents; Antimicrobial Cationic Peptides; Antineoplastic Agents; Azepines; Biological Products; Cell Proliferation; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Peptides; Structure-Activity Relationship
PubMed: 31257316
DOI: 10.1248/cpb.c19-00215