- The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase
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The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical r
- Bromba, Caleb M.,Mason, Jeremy W.,Brant, Michael G.,Chan, Tracy,Lunke, Martine D.,Petric, Martin,Boulanger, Martin J.,Wulff, Jeremy E.
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Read Online
- PYRIMIDINE AND PYRIDINE DERIVATIVES AND USE IN TREATMENT, AMELIORATION OR PREVENTION OF INFLUENZA THEREOF
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Provided herein is a compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which is useful in treating, ameliorating or preventing influenza.
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Page/Page column 263
(2017/12/28)
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- Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors
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Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.
- Wang, Peng-Cheng,Fang, Jim-Min,Tsai, Keng-Chang,Wang, Shi-Yun,Huang, Wen-I,Tseng, Yin-Chen,Cheng, Yih-Shyun E.,Cheng, Ting-Jen Rachel,Wong, Chi-Huey
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p. 5297 - 5310
(2016/07/06)
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- Process Development and GMP Production of a Potent NAE Inhibitor Pevonedistat
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A practical synthesis of a novel NEDD8-activating enzyme (NAE) inhibitor pevonedistat (MLN4924) is described. Key steps include an enantioselective synthesis of an amino-diol cyclopentane intermediate containing three chiral centers and a novel, regiosele
- Armitage, Ian,Elliott, Eric L.,Hicks, Frederick,Langston, Marianne,McCarron, Ashley,McCubbin, Quentin J.,Obrien, Erin,Stirling, Matt,Zhu, Lei
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p. 1299 - 1307
(2015/09/28)
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- ENHANCED ANTI-INFLUENZA AGENTS CONJUGATED WITH ANTI-INFLAMMATORY ACTIVITY
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Novel dual-targeted, bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents are disclosed. Exemplary drugs according to the invention include caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1), ZA-7-CA-amide (7) and ZA-7-Nap (43) for simultaneous inhibition of influenza virus neuraminidase and suppression of proinflammatory cytokines. Synthetic methods for preparation of these enhanced anti-influenza conjugate drugs are provided. The synthetic bifunctional ZA conjugates act synergistically towards protection of mice lethally infected by H1N1 or H5N1 influenza viruses. The efficacy of ZA-7-CA, ZA-7-CA-amide and ZA-7-Nap conjugates is much greater than the combination therapy of ZA with anti-inflammatory agents.
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Paragraph 0331
(2013/10/22)
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- Facile synthesis of the neuraminidase inhibitor peramivir
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An improved and convenient synthetic route for the synthesis of peramivir has been developed with a total 34% yield. The process was improved from previous methods in three key reaction steps including 1,3-dipolar cycloaddition, reductive ring cleavage of
- Jia, Fei,Hong, Juan,Sun, Ping-Hua,Chen, Jian-Xin,Chen, Wei-Min
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supporting information
p. 2641 - 2647
(2013/07/26)
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- PRODUCTION OF TRANS-4-AMINOCYCLOPENT-2-ENE-1-CARBOXYLIC ACID DERIVATIVES
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Methods of producing compositions of trans-4-amino-2-cyclopentene-1-carboxylic acid derivatives are described. Also described is an amine salt of a compound having formula A, having components present in both cis and trans structures.
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Page/Page column 9
(2011/02/24)
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- Process for the synthesis of E1 activating enzyme inhibitors
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The present invention provides processes and synthetic intermediates for the synthesis of 4-substituted ((1S,2S,4R)-2-hydroxy-4-{7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl sulfamates, which are E1 activating enzyme inhibitors, and are useful for t
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Page/Page column 24
(2009/03/07)
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- PROCESS FOR PREPARATION OF 4-N-SUBSTITUTED AMINO-2-AZA-1-OXABICYCLO 3.3.0]OCT-2-ENE-6-CARBOXYLIC ACID ESTERS AND PROCESS FOR PREPARATION OF THEIR INTERMEDIATES
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4-N-substituted amino-2-aza-1-oxabicyclo[3.3.0]oct-2-ene-6-carboxylic acid esters are produced by adding a Br?nsted acid to a mixture of a 2-azabicyclo[2.2.1]hept-5-en-3-one and an alcohol, thereby causing these components to react with each other to give a salt of cis-4-amino-2-cyclopentene-1-carboxylic acid ester, then allowing the salt of cis-4-amino-2-cyclopentene-1-carboxylic acid ester thus obtained to react with an amino-protecting group introducing compound in the presence of a base, thereby giving cis-4-N-substituted amino-2-cyclopentene-1-carboxylic acid ester, and then allowing this cis-4-N-substituted amino-2-cyclopentene-1-carboxylic acid ester to react with a hypohalogenite and an aldoxime.
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- Highly selective directed hydrogenation of enantiopure 4-(tert-butoxycarbonylamino)cyclopent-1-enecarboxylic acid methyl esters
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The use of both N-tert-butoxycarbonylamino- and hydroxyl-directed hydrogenation methodology to yield essentially single diastereomers of 3-(tert-butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid methyl esters and 3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid methyl esters is described. These results incorporate the first reported carbamate-directed hydrogenations of functionalised cyclopentenes.
- Smith, Mark E.B.,Derrien, Nadine,Lloyd, Michael C.,Taylor, Stephen J.C.,Chaplin, David A.,McCague, Raymond
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p. 1347 - 1350
(2007/10/03)
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- An efficient route to all eight stereoisomers of a tri-functionalised cyclopentane scaffold for drug discovery
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A route to all eight stereoisomers of 3-(tert-butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid methyl ester is presented; these products should prove to be valuable scaffolds in pharmaceutical discovery.
- Smith, Mark E.B.,Lloyd, Michael C.,Derrien, Nadine,Lloyd, Richard C.,Taylor, Stephen J.C.,Chaplin, David A.,Casy, Guy,McCague, Raymond
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p. 703 - 705
(2007/10/03)
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- Carbocyclic Sugar Amines: Synthesis and Stereochemistry of Racemic α- and β-Carbocyclic Ribofuranosylamine, Carbocyclic Lyxofuranosylamine, and Related Compounds
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The facile and stereoselective synthesis of racemic carbocyclic β-ribofuranosylamine, carbocyclic β-lyxofuranosylamine, and related 2,3-cis-dihydroxy carbocyclic pentofuranosylamines is reported.In addition, the synthesis, isolation, and base-catalyzed epimerization of methyl cis-4-aminocyclopent-2-enecarboxylate are described.The epimerization at C(1) followed by stereoselective cis hydroxylation provides for the first time access to the racemic carbocyclic α-pentofuranosylamines.
- Kam, Bernard L.,Oppenheimer, Norman J.
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p. 3268 - 3272
(2007/10/02)
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