Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: Synthesis and optimization studies of benzothiazine-substituted tetramic acids

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 19, 2009, Pages 5648-5651

  de Vicente, Javier ^a   Hendricks, Robert T ^a   Smith, David B ^a   Fell, Jay B ^a   Fischer, John ^b   Spencer, Stacey R ^b   Stengel, Peter J ^b   Mohr, Peter ^b   Robinson, John E ^b   Blake, James F ^b   Hilgenkamp, Ramona K ^a   Yee, Calvin ^a   Zhao, Junping ^a   Elworthy, Todd R ^a   Tracy, Jahari ^a   Chin, Elbert ^a   Li, Jim ^a   Lui, Al ^a   Wang, Beihan ^a   Oshiro, Connie ^a   Harris, Seth F ^a   Ghate, Manjiri ^a   Leveque, Vincent J P ^a   Najera, Isabel ^a   Pogam, Sophie Le ^a   Rajyaguru, Sonal ^a   Ao Ieong, Gloria ^a   Alexandrova, Ludmila ^a   Fitch, Bill ^a   Brandl, Michael ^a   Masjedizadeh, Mohammad ^a   Wu, Shao yong ^a   Keczer, Steve de ^a   Voronin, Tatyana ^a   more..

^a ROCHE BIOSCIENCE   (United States)

^b ARRAY BIOPHARMA INC   (United States)

Author keywords

Benzothiazine; Clearance; CYP 3A4; HCV; NS5B; Tetramic acid; Time dependent inactivation

Indexed keywords

CYTOCHROME P450 3A4; NONSTRUCTURAL PROTEIN 5B; NUCLEOTIDYLTRANSFERASE INHIBITOR; RNA POLYMERASE; TETRAMIC ACID DERIVATIVE; THIOACETAZONE;

ANIMAL EXPERIMENT; ARTICLE; DRUG ABSORPTION; DRUG BINDING; DRUG CLEARANCE; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ELECTRON; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; NONHUMAN; RAT; X RAY CRYSTALLOGRAPHY;

ANIMALS; ANTIVIRAL AGENTS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; HEPACIVIRUS; PYRROLIDINONES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZINES; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 69949100801     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.08.023     Document Type: Article

References (20)

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14. The enantiomeric purity of these compounds was retained through the synthetic sequence.
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17. A representative number of benzothiazine-substituted tetramic acids (11, 12, 14, 16, 27, 29, 30) were also evaluated in a GT-1a replicon assay. This class of compounds had a minimal loss in inhibitory activity of four to 10-fold relative to our standard GT-1b replicon assay.
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19. 50 0.024 μM.
20. The synthesis of C-5 fluoro substituted benzothiazine 30 was accomplished following the sequence shown in Scheme 1 but starting from 4-fluoro-6-nitrobenzothiazole.