2. Academic Validation
  3. Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines

Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines

  • J Med Chem. 2009 Mar 26;52(6):1659-69. doi: 10.1021/jm8010965.
Rolf Wagner 1,  Daniel P Larson,  David W A Beno,  Todd D Bosse,  John F Darbyshire,  Yi Gao,  Bradley D Gates,  Wenping He,  Rodger F Henry,  Lisa E Hernandez,  Douglas K Hutchinson,  Wen W Jiang,  Warren M Kati,  Larry L Klein,  Gennadiy Koev,  William Kohlbrenner,  A Chris Krueger,  Jinrong Liu,  Yaya Liu,  Michelle A Long,  Clarence J Maring,  Sherie V Masse,  Tim Middleton,  Debra A Montgomery,  John K Pratt,  Patricia Stuart,  Akhteruzzaman Molla,  Dale J Kempf
Affiliations

Affiliation

  • 1 Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064, USA. rolf.wagner@abbott.com
PMID: 19226162 DOI: 10.1021/jm8010965
Abstract

The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon Cell Culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.

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