Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 22, 2009, Pages 6404-6412

  Ruebsam, Frank ^a   Murphy, Douglas E ^a   Tran, Chinh V ^a   Li, Lian Sheng ^a   Zhao, Jingjing ^a   Dragovich, Peter S ^a   McGuire, Helen M ^a   Xiang, Alan X ^a   Sun, Zhongxiang ^a   Ayida, Benjamin K ^a   Blazel, Julie K ^a   Kim, Sun Hee ^a   Zhou, Yuefen ^a   Han, Qing ^a   Kissinger, Charles R ^a   Webber, Stephen E ^a   Showalter, Richard E ^a   Shah, Amit M ^a   Tsan, Mei ^a   Patel, Rupal A ^a   Thompson, Peggy 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   Khandurina, Julia ^a   Brooks, Jennifer ^a   Okamoto, Ellen ^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; Palm binding site

Indexed keywords

ANTIVIRUS AGENT; MYOTONIC DYSTROPHY PROTEIN KINASE; NONSTRUCTURAL PROTEIN 5B; TRICYCLIC 5,6 DIHYDRO 1H PYRIDIN 2 ONE; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG STRUCTURE; GENOTYPE; HEPATITIS C VIRUS; IN VITRO STUDY; IN VIVO STUDY; METABOLISM;

ANTIVIRAL AGENTS; BIOLOGICAL AVAILABILITY; CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; GENOTYPE; HEPACIVIRUS; HEPATITIS C; MOLECULAR STRUCTURE; RNA REPLICASE; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 71049181073     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.09.045     Document Type: Article

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56. The optical purity (ee) of compound 2c prepared from anhydride 9 via enantioselective desymmetrization was rigorously determined by chiral HPLC to be >98.5% (using enantiomer 2e and racemic analog 2a as HPLC references). This result also established that the chemistries depicted in Scheme 1 which transform β-amino acid esters 7 to inhibitors 2 do not result in significant racemization. The optical purities of other chiral inhibitors 2, 4, and 5 described in this work were therefore assumed to be similar to those of the corresponding starting materials (typically >96% ee).
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