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Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: Synthesis and structure–activity relationships of benzothiazine-substituted quinolinediones

2009; Elsevier BV; Volume: 19; Issue: 13 Linguagem: Inglês

10.1016/j.bmcl.2009.05.004

1464-3405

Javier de Vicente, R. Hendricks, David B. Smith, Jay B. Fell, John P. Fischer, Stacey R. Spencer, Peter J. Stengel, Peter J. Mohr, John Robinson, James F. Blake, Ramona Hilgenkamp, Calvin Yee, George M. Adjabeng, Todd R. Elworthy, Jahari Laurant Tracy, Elbert Chin, Jimmy Li, Beihan Wang, Joe T. Bamberg, Rebecca A. Stephenson, Connie Oshiro, Seth F. Harris, M. Ghate, Vincent Lévêque, Isabel Nájera, Sophie Le Pogam, Sonal Rajyaguru, Gloria Ao-Ieong, L. А. Alexandrova, Susan Larrabee, Michael Brandl, Andrew J. Briggs, Sunil Sukhtankar, Robert Farrell, Brian Xu,

Quinazolinone synthesis and applications

A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.