5,5′- and 6,6′-Dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 21, 2009, Pages 6047-6052

  Ellis, David A ^a   Blazel, Julie K ^a   Tran, Chinh V ^a   Ruebsam, Frank ^a   Murphy, Douglas E ^a   Li, Lian Sheng ^a   Zhao, Jingjing ^a   Zhou, Yuefen ^a   McGuire, Helen M ^a   Xiang, Alan X ^a   Webber, Stephen E ^a   Zhao, Qiang ^a   Han, Qing ^a   Kissinger, Charles R ^a   Lardy, Matthew ^a   Gobbi, Alberto ^a   Showalter, Richard E ^a   Shah, Amit M ^a   Tsan, Mei ^a   Patel, Rupal A ^a   LeBrun, Laurie A ^a   Kamran, Ruhi ^a   Bartkowski, Darian M ^a   Nolan, Thomas G ^a   Norris, Daniel A ^a   Sergeeva, Maria V ^a   Kirkovsky, Leo ^a   more..

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

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

Indexed keywords

5,5' DIALKYL 5,6 DIHYDRO 1H PYRIDIN 2 ONE; 6,6' DIALKYL 5,6 DIHYDRO 1H PYRIDIN 2 ONE; ANTIVIRUS AGENT; BICYCLIC 5,6 DIHYDRO 1H PYRIDIN 2 ONE; NONSTRUCTURAL PROTEIN 5B; RNA DIRECTED DNA POLYMERASE INHIBITOR; UNCLASSIFIED DRUG; ENZYME INHIBITOR; NS 5 PROTEIN, HEPATITIS C VIRUS; NS-5 PROTEIN, HEPATITIS C VIRUS; PYRIDONE DERIVATIVE; RNA DIRECTED RNA POLYMERASE; VIRUS PROTEIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL ACTIVITY; ARTICLE; CELL CULTURE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG HALF LIFE; DRUG METABOLISM; DRUG STABILITY; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; IN VITRO STUDY; LIVER MICROSOME; NONHUMAN; ANIMAL; BINDING SITE; CHEMISTRY; DRUG ANTAGONISM; ENZYMOLOGY; MACACA; METABOLISM; STRUCTURE ACTIVITY RELATION; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

HEPATITIS C VIRUS;

ANIMALS; ANTIVIRAL AGENTS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HEPACIVIRUS; HUMANS; MACACA FASCICULARIS; MICROSOMES, LIVER; PYRIDONES; RNA REPLICASE; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

EID: 71749114009     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.09.051     Document Type: Article

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24. Chiral analysis was performed on the racemic mixtures initially to verify separation of the enantiomers and to ensure that concentrations of each were approximately equal. After exposure of the racemic mixture to HLM, chiral analysis was performed again. In all cases, after exposure, the area under one peak (as determined by chiral HPLC) was substantially lower than the other. Chiral HPLC-analysis was performed using the Chiralpak (Chiral Technologies Inc.) column AS-RH, 2.1 × 150 mm, 5 μm, λ = 312 nm with the following binary gradient conditions: solvent A: 0.1% formic acid in water, solvent B: 0.1% formic acid in acetonitrile. Injected 10 μL of sample dissolved in 50% methanol-50% water (0.1 mg/mL). 55-95%B in 5 min followed by 0.5 min at 95%B (flow rate 0.3 mL/min). Compound mass was verified by analyzing the eluent by either (+)-ES or APCI (+) LC-MS.