- Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies
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The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents.
- Ye, Jiqing,Yang, Xiao,Xu, Min,Chan, Paul Kay-sheung,Ma, Cong
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- ALKALOID AMINOESTER DERIVATIVES AND MEDICINAL COMPOSITION THEREOF
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The present invention relates to alkaloid aminoester derivatives acting as muscarinic receptor antagonists, processes for their preparation, compositions comprising them and therapeutic uses thereof.
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Page/Page column 62-63
(2012/01/13)
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- New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity
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A series of 3- and 5-aryl-1,2,4-oxadiazole derivatives were prepared and tested for anticonvulsant activity in a variety of models. These 1,2,4-oxadiazoles exhibit considerable activity in both pentylenetetrazole (PTZ) and maximal electroshock seizure (MES) models. Compound 10 was protective in the PTZ model in rats with an oral ED50 of 25.5 mg/kg and in the MES model in rats with an oral ED50 of 14.6 mg/kg. Neurotoxicity (rotarod) was observed with an ED50 of 335 mg/kg. We found several oxadiazoles that acted as selective GABA potentiating compounds with no interaction to the benzodiazepine binding site.
- Lankau, Hans-Joachim,Unverferth, Klaus,Grunwald, Christian,Hartenhauer, Helge,Heinecke, Kristina,Bernoester, Katrin,Dost, Rita,Egerland, Ute,Rundfeldt, Chris
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p. 873 - 879
(2008/02/12)
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- Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists
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A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)- xanthine derivatives as A2B-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A2B, A 1, A2A, and A3-AdoRs. 8-(1-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)-dione (4) displayed high affinity (Ki = 1 nM) and selectivity for the A2B-AdoR versus A1, A2A, and A 3-AdoRs (A1/A2B, A2A/A2B, and A3/A2B selectivity ratios of 370, 1100, and 480, respectively). The synthesis and SAR of this novel class of compounds are presented herein.
- Elzein, Elfatih,Kalla, Rao,Li, Xiaofen,Perry, Thao,Parkhill, Eric,Palle, Venkata,Varkhedkar, Vaibahv,Gimbel, Art,Zeng, Dewan,Lustig, David,Leung, Kwan,Zablocki, Jeff
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p. 302 - 306
(2007/10/03)
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- The discovery of a selective, high affinity A2B adenosine receptor antagonist for the potential treatment of asthma
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Adenosine has been suggested to play a role in asthma, possibly via activation of A2B adenosine receptors on mast cells and other pulmonary cells. We describe our initial efforts to discover a xanthine based selective A2B AdoR antagonist that resulted in the discovery of CVT-5440, a high affinity A2B AdoR antagonist with good selectivity (A2B AdoR Ki = 50 nM, selectivity A1 > 200: A2A > 200: A3 > 167).
- Zablocki, Jeff,Kalla, Rao,Perry, Thao,Palle, Venkata,Varkhedkar, Vaibhav,Xiao, Dengming,Piscopio, Anthony,Maa, Tenning,Gimbel, Art,Hao, Jia,Chu, Nancy,Leung, Kwan,Zeng, Dewan
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p. 609 - 612
(2007/10/03)
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- CVT-4325: A potent fatty acid oxidation inhibitor with favorable oral bioavailability
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New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the 'Western Portion' of the molecule. SAR studies led to the discovery of CVT-4325, a potent FOXi (IC50 = 380 nM, rat mitochondria) with favorable PK properties (F = 93%, t1/2 = 13.6 h, dog). New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the 'Western Portion' of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC50 = 380 nM rat mitochondria) with favorable PK properties (F = 93%, t1/2 = 13.6 h, dog).
- Elzein, Elfatih,Ibrahim, Prabha,Koltun, Dmitry O.,Rehder, Ken,Shenk, Kevin D.,Marquart, Timothy A.,Jiang, Bob,Li, Xiaofen,Natero, Reina,Li, Yuan,Nguyen, Marie,Kerwar, Suresh,Chu, Nancy,Soohoo, Daniel,Hao, Jia,Maydanik, Victoria Y.,Lustig, David A.,Zeng, Dewan,Leung, Kwan,Zablocki, Jeff A.
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p. 6017 - 6021
(2007/10/03)
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- ARYL AND HETEROARYL ALKOXYNAPHTHALENE DERIVATIVES
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Compounds of the formula wherein R1, R2, R4, R23, R24, R25 and R26 are defined as in the specification. These compounds are useful psychotherapeutics and are potent serotonin (5-HT1) agonists and antagonists.
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- Aryl and heteroaryl alkoxynaphthalene derivatives
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Compounds of the formula wherein R1, R2, R4, R23, R24, R25 and R26 are defined as in the specification. These compounds are useful psychotherapeutics and are potent serotonin (5-HT1) agonists and antagonists.
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- Use of naphthalene derivatives in treating lung carcinoma
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A method of inhibiting cell growth in human small cell lung carcinoma comprising administering to a mammal in need of such treatment a cell growth inhibitory amount of a compound of the formula STR1
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- Use of naphthalene derivatives in treating lung carcinoma
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The use of a compound of the formula or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting cell growth in human small cell lung carcinoma through inhibition of the 5HT1D receptor.
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