William J. Watkins†

Publications (3)7.49 Total impact

• Article: Preclinical characterization of GS-9669, a Thumb Site II Inhibitor of the Hepatitis C Virus NS5B Polymerase.

  Martijn Fenaux, Stacey Eng, Stephanie A Leavitt, Tu-Jen Lee, Eric M Mabery, Yang Tian, Daniel Byun, Eda Canales, Michael O Clarke, Edward Doerffler, [......], Jennifer Zhang, Mike Matles, Bernard P Murray, Judy Mwangi, Jingyu Zhang, Ahmad Hashash, Steve H Krawczyk, Alison M Bidgood, Todd C Appleby, William J Watkins
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  ABSTRACT: GS-9669 is a highly-optimized Thumb Site II non-nucleoside inhibitor of the hepatitis C (HCV) virus RNA polymerase, with binding affinity of 1.35 nM for the genotype 1b protein. It is a selective inhibitor of HCV RNA replication with mean 50% effective concentration (EC(50)) of ≤11 nM in genotype 1 and 5 replicon assays, but lacks useful activity against genotypes 2-4. The M423T mutation is readily generated clinically upon monotherapy with the Thumb Site II inhibitors filibuvir and lomibuvir, and it is notable that GS-9669 exhibited only 3-fold loss in potency against this variant in the genotype 1b replicon. Rather than M423T, resistance predominantly tracks to residues R422K and L419M, and I482L, in GT1b and 1a replicons, respectively. GS-9669 exhibited at least additive activity in combination with agents encompassing four other direct modes of action (NS3 protease, NS5A, NS5B via an alternative allosteric binding site, and NS5B nucleotide), as well as with interferon-α or ribavirin, in replicon assays. It exhibited high metabolic stability in in vitro human liver microsomal assays which, in combination with its pharmacokinetic profiles in rat, dog and two monkey species, is predictive of human good pharmacokinetics. GS-9669 is well suited for combination with other orally active, direct-acting antiviral agents in the treatment of genotype 1 chronic HCV infection.
  Antimicrobial Agents and Chemotherapy 11/2012; · 4.84 Impact Factor
• Article: Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors.

  Eda Canales, Joseph S Carlson, Todd Appleby, Martijn Fenaux, Johnny Lee, Yang Tian, Neeraj Tirunagari, Melanie Wong, William J Watkins
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  ABSTRACT: The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent binding affinities and encouraging levels of cellular potency.
  Bioorganic & medicinal chemistry letters 05/2012; 22(13):4288-92. · 2.65 Impact Factor
• Article: Optimization of Pharmacokinetics through Manipulation of Physicochemical Properties in a Series of HCV Inhibitors

  Scott E. Lazerwith*†, Gina Bahador§, Eda Canales†, Guofeng Cheng§, Lee Chong†, Michael O. Clarke†, Edward Doerffler†, Eugene J. Eisenberg‡, Jaclyn Hayes‡, Bing Lu‡, [......], Margaret Robinson§, Robert G. Strickley, Megan Tessler, Neeraj Tirunagari§, Jianhong Wang‡, Yujin Wang‡, Jennifer R. Zhang†, Xubin Zheng‡, Weidong Zhong§, William J. Watkins†
  ACS Med. Chem. Lett. 01/2011; 2(10):715-719.