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

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

  • Bioorg Med Chem Lett. 2009 Nov 15;19(22):6404-12. doi: 10.1016/j.bmcl.2009.09.045.
Frank Ruebsam 1,  Douglas E Murphy,  Chinh V Tran,  Lian-Sheng Li,  Jingjing Zhao,  Peter S Dragovich,  Helen M McGuire,  Alan X Xiang,  Zhongxiang Sun,  Benjamin K Ayida,  Julie K Blazel,  Sun Hee Kim,  Yuefen Zhou,  Qing Han,  Charles R Kissinger,  Stephen E Webber,  Richard E Showalter,  Amit M Shah,  Mei Tsan,  Rupal A Patel,  Peggy A Thompson,  Laurie A Lebrun,  Huiying J Hou,  Ruhi Kamran,  Maria V Sergeeva,  Darian M Bartkowski,  Thomas G Nolan,  Daniel A Norris,  Julia Khandurina,  Jennifer Brooks,  Ellen Okamoto,  Leo Kirkovsky
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Anadys Pharmaceuticals, Inc., 5871 Oberlin Drive, Suite 200, San Diego, CA 92121, USA. fruebsam@anadyspharma.com
PMID: 19818610 DOI: 10.1016/j.bmcl.2009.09.045
Abstract

A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro Antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.

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