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Antimicrobial Agents and Chemotherapy, May 2002, p. 1394-1401, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1394-1401.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

DPC 817: a Cytidine Nucleoside Analog with Activity against Zidovudine- and Lamivudine-Resistant Viral Variants

Raymond F. Schinazi,1* John Mellors,2 Holly Bazmi,2 Sharon Diamond,3 Sena Garber,3 Karen Gallagher,3 Romas Geleziunas,3 Ron Klabe,3 Michael Pierce,3 Marlene Rayner,3 Jing-Tao Wu,3 Hangchun Zhang,3 Jennifer Hammond,2 Lee Bacheler,3 Douglas J. Manion,3 Michael J. Otto,4 Lieven Stuyver,4 George Trainor,3 Dennis C. Liotta,1 and Susan Erickson-Viitanen3*

Pharmasset, Inc., Tucker, Georgia 30084,4 Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Atlanta, Georgia 30033,1 Department of Medicine and Infectious Diseases and Microbiology, University of Pittsburgh, and Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15261,2 Departments of Virology, Drug Metabolism, and Chemistry, The Dupont Pharmaceuticals Company,,{dagger} Wilmington, Delaware 19880,{dagger}

Received 22 August 2001/ Returned for modification 20 November 2001/ Accepted 31 January 2002

Highly active antiretroviral therapy (HAART) is the standard treatment for infection with the human immunodeficiency virus (HIV). HAART regimens consist of protease inhibitors or nonnucleoside reverse transcriptase inhibitors combined with two or more nucleoside reverse transcriptase inhibitors (NRTIs). DPC 817, 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (PSI 5582 D-D4FC) is a potent inhibitor of HIV type 1 replication in vitro. Importantly, DPC 817 retains activity against isolates harboring mutations in the reverse transcriptase gene that confer resistance to lamivudine (3TC) and zidovudine (AZT), which are frequent components of initial HAART regimens. DPC 817 combines this favorable resistance profile with rapid uptake and conversion to the active metabolite DPC 817-triphosphate, which has an intracellular half-life of 13 to 17 h. Pharmacokinetics in the rhesus monkey suggest low clearance of parent DPC 817 and a plasma half-life longer than that of either AZT or 3TC. Together, these properties suggest that DPC 817 may be useful as a component of HAART regimens in individuals with resistance to older NRTI agents.

* Corresponding author. Present address for S. K. Viitanen: c/o Pharmasset, Inc., 1860 Montreal Rd., Tucker, GA 30084. Phone: (678) 395-0050. Fax: (302) 685-4509. E-mail: skviitanen{at}aol.com. Mailing address for R. Schinazi: VA Medical Center/Emory University, Decatur, GA 30033. Mailing address for R. Schinazi: VA Medical Center/Emory University, Decatur, GA 30033. Phone: (404) 728-7711. Fax: (404) 728-7726. E-mail: rschina{at}emory.edu.

Now Bristol-Myers Squibb Pharmaceuticals Company.

Antimicrobial Agents and Chemotherapy, May 2002, p. 1394-1401, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1394-1401.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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