Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 14, 2008, Pages 4181-4185

  Kim, Sun Hee ^a   Tran, Martin T ^a   Ruebsam, Frank ^a   Xiang, Alan X ^a   Ayida, Benjamin ^a   McGuire, Helen ^a   Ellis, David ^a   Blazel, Julie ^a   Tran, Chinh V ^a   Murphy, Douglas E ^a   Webber, Stephen E ^a   Zhou, Yuefen ^a   Shah, Amit M ^a   Tsan, Mei ^a   Showalter, Richard E ^a   Patel, Rupal ^a   Gobbi, Alberto ^a   LeBrun, Laurie A ^a   Bartkowski, Darian M ^a   Nolan, Thomas G ^a   Norris, Daniel A ^a   Sergeeva, Maria V ^a   Kirkovsky, Leo ^a   Zhao, Qiang ^a   Han, Qing ^a   Kissinger, Charles R ^a   more..

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

1,1 Dioxoisothiazole; Benzo b thiophene 1,1 dioxide; DMPK properties; Hepatitis C virus (HCV); NS5B inhibitors; X ray co crystal structures

Indexed keywords

1,1 DIOXOISOTHIAZOLE DERIVATIVE; ANTIVIRUS AGENT; BENZOTHIOPHENE DERIVATIVE; ISOTHIAZOLE DERIVATIVE; NONSTRUCTURAL PROTEIN 5B; THIANAPHTHENE S,S DIOXIDE DERIVATIVE;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONCENTRATION RESPONSE; CRYSTAL STRUCTURE; DRUG CLEARANCE; DRUG DESIGN; DRUG SYNTHESIS; ENZYME INHIBITION; HEPATITIS C VIRUS; IC 50; MONKEY; NONHUMAN; REACTION ANALYSIS; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION;

ANTIVIRAL AGENTS; CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ENZYME INHIBITORS; GENOTYPE; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, CHEMICAL; MOLECULAR CONFORMATION; RNA, VIRAL; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; THIOPHENES; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 47149118318     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.05.083     Document Type: Article

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15. 2 at pH 7.6, and inhibitors at concentrations of 2 mM. Diffraction data were collected to a resolution of 2.3 Å for compound 3. Diffraction data for 3 were collected on beamline 14IDB at the Advanced Photon Source at Argonne National Laboratory. Crystal structures discussed in this paper have been deposited in the Protein Databank (www.rcsb.org) with entry codes: 3D28 and 3BSC. Full details of structure determination are given in the respective PDB entries.
16. 2 at pH 7.6, and inhibitors at concentrations of 5 mM. Diffraction data were collected to a resolution of 2.2 Å for compound 34. Diffraction data for 34 were collected on beamline 14IDB at the Advanced Photon Source at Argonne National Laboratory. Crystal structures discussed in this paper have been deposited in the Protein Databank (www.rcsb.org) with entry codes: 3D5M. Full details of structure determination are given in the respective PDB entries.
17. As part of a strategy to rapidly evaluate the oral PK properties of the NS5B inhibitors under study, the corresponding PK data following IV administration of the described compounds were not obtained.
18. During the course of this study, similar HCV NS5B inhibitors were described in the patent literature. See: Blake, J. F.; Fell, J. B.; Fischer, J. P.; Hendricks, R. T.; Spencer, S. R.; Stengel, P. J. U.S. Patent Application 2006/0252785, 2006.