5,6-Dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 2, 2009, Pages 451-458

  Ruebsam, Frank ^a   Tran, Chinh V ^a   Li, Lian Sheng ^a   Kim, Sun Hee ^a   Xiang, Alan X ^a   Zhou, Yuefen ^a   Blazel, Julie K ^a   Sun, Zhongxiang ^a   Dragovich, Peter S ^a   Zhao, Jingjing ^a   McGuire, Helen M ^a   Murphy, Douglas E ^a   Tran, Martin T ^a   Stankovic, Nebojsa ^a   Ellis, David A ^a   Gobbi, Alberto ^a   Showalter, Richard E ^a   Webber, Stephen E ^a   Shah, Amit M ^a   Tsan, Mei ^a   Patel, Rupal A ^a   LeBrun, Laurie A ^a   Hou, Huiying J ^a   Kamran, Ruhi ^a   Sergeeva, Maria V ^a   Bartkowski, Darian M ^a   Nolan, Thomas G ^a   Norris, Daniel A ^a   Kirkovsky, Leo ^a   more..

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

5,6 Dihydro 1H pyridin 2 ones; Hepatitis C virus (HCV); Non nucleoside NS5B inhibitor; NS5B polymerase; Small molecule

Indexed keywords

5,6 DIHYDRO 1H PYRIDIN 2 ONE DERIVATIVE; ANTIVIRUS AGENT; NONSTRUCTURAL PROTEIN 5B; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; GENOTYPE; HEPATITIS C VIRUS; IC 50; IN VITRO STUDY; MONKEY; NONHUMAN; REPLICON; SINGLE DRUG DOSE;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; DNA-DIRECTED RNA POLYMERASES; ENZYME INHIBITORS; HAPLORHINI; PYRIDONES; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 57749112840     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.11.048     Document Type: Article

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32. 1H NMR spectra that were often broad and difficult to rigorously characterize. Based on the LC-MS analysis of these molecules and the HPLC, LC-MS, and NMR data associated with compounds 4a-4c, we believe that the more polar sulfonamide-containing inhibitors were prepared predominantly as the cis-isomers (which exist in multiple tautomeric forms in polar organic solvents) and that they contain no more than 10% of the corresponding trans-isomers (if any).
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38. We cannot exclude the possibility that the improved in vivo properties of compounds 4 result from increased aqueous solubility that was not detected in our high-throughput (biochemical) solubility assessments.