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Phosphoramidate ProTides of 2′-C-Methylguanosine as Highly Potent Inhibitors of Hepatitis C Virus. Study of Their in Vitro and in Vivo Properties

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Christopher McGuigan*†, Arnaud Gilles†, Karolina Madela†, Mohamed Aljarah†, Sabrina Holl†, Sarah Jones†, John Vernachio‡, Jeff Hutchins‡, Brenda Ames‡, K. Dawn Bryant‡, Elena Gorovits‡, Babita Ganguly‡, Damound Hunley‡, Andrea Hall‡, Alexander Kolykhalov‡, Yule Liu‡, Jerry Muhammad‡, Nicholas Raja‡, Robin Walters‡, Jin Wang‡, Stanley Chamberlain‡ and Geoffrey Henson‡

^† Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, U.K.

^‡ Inhibitex Inc., 9005 Westside Parkway, Alpharetta, Georgia 30004

J. Med. Chem., 2010, 53 (13), pp 4949–4957

DOI: 10.1021/jm1003792

Publication Date (Web): June 8, 2010

*To whom correspondence should be addressed. Phone/Fax: +44 29 20874537. E-mail: mcguigan@cardiff.ac.uk.

Section:

Amino Acids, Peptides, and Proteins

Abstract

Hepatitis C virus infection constitutes a serious health problem in need of more effective therapies. Nucleoside analogues with improved exposure, efficacy, and selectivity are recognized as likely key components of future HCV therapy. 2′-C-Methylguanosine triphosphate has been known as a potent inhibitor of HCV RNA polymerase for some time, but the parent nucleoside is only moderately active due to poor intracellular phosphorylation. We herein report the application of phosphoramidate ProTide technology to bypass the rate-limiting initial phosphorylation of this nucleoside. Over 30 novel ProTides are reported, with variations in the aryl, ester, and amino acid regions. l-Alanine compounds are recognized as potent and selective inhibitors of HCV in replicon assay but lack rodent plasma stability despite considerable ester variation. Amino acid variation retaining the lead benzyl ester moiety gives an increase in rodent stability but at the cost of potency. Finally l-valine esters with ester variation lead to potent, stable compounds. Pharmacokinetic studies on these agents in the mouse reveal liver exposure to the bioactive triphosphate species following single oral dosing. Systemic exposure of the ProTide and parent nucleoside are low, indicating possible low toxicity in vivo, while liver concentrations of the active species may be predictive of efficacy in the clinic. This represents one of the most thorough cross-species studies of ProTides to date.

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This article has been cited by 2 ACS Journal articles (2 most recent appear below).

Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase
Michael J. Sofia, Wonsuk Chang, Phillip A. Furman, Ralph T. Mosley, and Bruce S. Ross
Journal of Medicinal Chemistry2012 Article ASAP
- Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase
  Michael J. Sofia, Wonsuk Chang, Phillip A. Furman, Ralph T. Mosley, and Bruce S. Ross
  Journal of Medicinal Chemistry2012 Article ASAP
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links
Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection
Wonsuk Chang, Donghui Bao, Byoung-Kwon Chun, Devan Naduthambi, Dhanapalan Nagarathnam, Suguna Rachakonda, P. Ganapati Reddy, Bruce S. Ross, Hai-Ren Zhang, Shalini Bansal, Christine L. Espiritu, Meg Keilman, Angela M. Lam, Congrong Niu, Holly Micolochick Steuer, Phillip A. Furman, Michael J. Otto, and Michael J. Sofia
ACS Medicinal Chemistry Letters2011 2 (2), 130-135
- Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection
  Wonsuk Chang, Donghui Bao, Byoung-Kwon Chun, Devan Naduthambi, Dhanapalan Nagarathnam, Suguna Rachakonda, P. Ganapati Reddy, Bruce S. Ross, Hai-Ren Zhang, Shalini Bansal, Christine L. Espiritu, Meg Keilman, Angela M. Lam, Congrong Niu, Holly Micolochick Steuer, Phillip A. Furman, Michael J. Otto, and Michael J. Sofia
  ACS Medicinal Chemistry Letters2011 2 (2), 130-135
  Hepatitis C virus afflicts approximately 180 million people worldwide, and the development of direct acting antivirals may offer substantial benefit compared to the current standard of care. Accordingly, prodrugs of 2′-deoxy-2′-fluoro-2′-C-methylguanosine ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links