3H2L

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

Ruebsam, F., Murphy, D.E., Tran, C.V., Li, L.S., Zhao, J., Dragovich, P.S., McGuire, H.M., Xiang, A.X., Sun, Z., Ayida, B.K., Blazel, J.K., Kim, S.H., Zhou, Y., Han, Q., Kissinger, C.R., Webber, S.E., Showalter, R.E., Shah, A.M., Tsan, M., Patel, R.A., Thompson, P.A., Lebrun, L.A., Hou, H.J., Kamran, R., Sergeeva, M.V., Bartkowski, D.M., Nolan, T.G., Norris, D.A., Khandurina, J., Brooks, J., Okamoto, E., Kirkovsky, L.

(2009) Bioorg Med Chem Lett 19: 6404-6412

• PubMed: 19818610 Search on PubMed
• DOI: https://doi.org/10.1016/j.bmcl.2009.09.045
• Primary Citation of Related Structures:  
  3H2L


• PubMed 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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Organizational Affiliation: 

Department of Medicinal Chemistry, Anadys Pharmaceuticals, Inc., 5871 Oberlin Drive, Suite 200, San Diego, CA 92121, USA. fruebsam@anadyspharma.com