- TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Inflammation
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TWIK-related K+ (TREK) channels are potential analgesic targets. However, selective activators for TREK with both defined action mechanism and analgesic ability for chronic pain have been lacking. Here, we report (1S,3R)-3-((4-(6-methylbenzo[d]
- Qiu, Yunguang,Huang, Lu,Fu, Jie,Han, Chenxia,Fang, Jing,Liao, Ping,Chen, Zhuo,Mo, Yiqing,Sun, Peihua,Liao, Daqing,Yang, Linghui,Wang, Jing,Zhang, Qiansen,Liu, Jin,Liu, Feng,Liu, Tingting,Huang, Wei,Yang, Huaiyu,Jiang, Ruotian
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p. 3665 - 3677
(2020/04/30)
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- Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists
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2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [35S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([35S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
- Geyer, Roland,Nordemann, Uwe,Strasser, Andrea,Wittmann, Hans-Joachim,Buschauer, Armin
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p. 3452 - 3470
(2016/05/19)
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- BENZAMIDE IMIDAZOPYRAZINE BTK INHIBITORS
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Provided are Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, or their use in therapy.
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Page/Page column 58
(2016/07/27)
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- Highly enantioselective desymmetrizations of meso-anhydrides
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Readily available, low molecular cyclohexane-based organocatalysts promote highly enantioselective desymmetrizations of cyclic meso-anhydrides applying alcohols and benzyl mercaptan as nucleophiles. Both succinic and glutaric anhydrides furnished the corresponding products with up to 96% ee in mostly quantitative yields.
- Schmitt, Ellen,Schiffers, Ingo,Bolm, Carsten
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experimental part
p. 6349 - 6357
(2010/10/03)
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- Synthesis and antiviral activities of some novel carbocyclic nucleosides
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cis-3-Aminomethylcyclopentylmethanol (4), prepared from norbornene (5) in four steps and 51% overall yield, was used as a precursor in the synthesis of carbocylic nucleosides 13 - 18 containing guanine and 8-azaguanine bases. None of these compounds had a
- Carmen Balo,Fernandez, Franco,Lens, Evangelina,Lopez, Carmen,De Clercq, Erik,Andrei, Graciela,Snoeck, Robert,Baizarini, Jan
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p. 1335 - 1346
(2007/10/03)
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- Chemoenzymatic Enantioselective Synthesis of Amidinomycin
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We report the first asymmetric synthesis of amidinomycin, an antiviral antibiotic metabolite.Amidinomycin of high enantiomeric purity (ee 91percent) was prepared from norbornylene in 8 steps.The key step is an enzymatic discrimination of enantiotopic groups in meso cis-1,3-dicarbomethoxycyclopentane or in meso cis-cyclopentane-1,3-dicarboxylic acid anhydride.
- Chenevert, Robert,Lavoie, Michele,Courchesne, Gabriel,Martin, Richard
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- Bridged bicyclic imides as anxiolytics and antidepressants
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A series of bridged bicyclic imide compounds having a 4-(4-[2-pyrimidinyl]-1-piperazinyl)butyl group attached to the imide nitrogen are useful for alleviating the symptoms of anxiety and depression in human subjects.
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- Enantioselective synthesis of (+) and (-)-cis-3-aminocyclopentanecarboxylic acids by enzymatic asymmetrization
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Both enantiomers of cis-3-aminocyclopentanecarboxylic acid (GABA analogs, inhibitory neurotransmitter) have been prepared via enzymatic asymmetrization of cis -1,3-cyclopentanedicarboxylic acid.
- Chenevert,Martin
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p. 199 - 200
(2007/10/02)
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- Bridged bicyclic imides as anxiolytics and antidepressants
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A series of bridged bicyclic imide compounds having a 4-(4-[2-pyrimidinyl]-1-piperazinyl)butyl group attached to the imide nitrogen are useful for alleviating the symptoms of anxiety and depression in human subjects.
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