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Antimicrobial Agents and Chemotherapy, October 2004, p. 3944-3953, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3944-3953.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties

David B. Olsen,1* Anne B. Eldrup,2 Linda Bartholomew,3 Balkrishen Bhat,2 Michele R. Bosserman,1 Alessandra Ceccacci,3 Lawrence F. Colwell,4 John F. Fay,1 Osvaldo A. Flores,1 Krista L. Getty,1 Jay A. Grobler,1 Robert L. LaFemina,1 Eric J. Markel,1 Giovanni Migliaccio,3 Marija Prhavc,2 Mark W. Stahlhut,1 Joanne E. Tomassini,1 Malcolm MacCoss,4 Daria J. Hazuda,1 and Steven S. Carroll1

Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania,1 Department of Medicinal Chemistry, Isis Pharmaceuticals, Carlsbad, California,2 Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Italy,3 Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey4

Received 13 March 2004/ Returned for modification 13 May 2004/ Accepted 8 June 2004

Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2'-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5'-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2'-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2'-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2'-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.

* Corresponding author. Mailing address: Merck and Co., WP26-265, West Point, PA 19486. Phone: (215) 652-5250. Fax: (215) 993-2330. E-mail: david_olsen{at}merck.com.

Antimicrobial Agents and Chemotherapy, October 2004, p. 3944-3953, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3944-3953.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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