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Antimicrobial Agents and Chemotherapy, January 1999, p. 190-193, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Metabolic Studies on BMS-200475, a New Antiviral Compound Active against Hepatitis B Virus

Gregory Yamanaka,1,* Todd Wilson,1 Steven Innaimo,1 Gregory S. Bisacchi,2 Peter Egli,2 J. Kent Rinehart,2 Robert Zahler,2 and Richard J. Colonno1

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660,1 and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-40002

Received 17 March 1998/Returned for modification 25 June 1998/Accepted 31 October 1998

BMS-200475 was recently shown to have potent antiviral activity against hepatitis B virus (50% effective concentration = 3.7 nM; 50% cytotoxic concentration = 30 µM). In metabolic studies in both HepG2 and hepatitis B virus-transfected 2.2.15 human hepatoma cell lines, the metabolism was similar, the primary products being the di- and triphosphates. The accumulation of triphosphate was rapid and detectable down to a 5 nM concentration of added drug. When cells were labeled at 25 µM, the intracellular triphosphate concentration attained 30 pmol/106 cells (~30 µM). The intracellular half-life of the triphosphate was about 15 h. Compared with five other nucleoside analogs of medical interest (lamivudine, penciclovir, ganciclovir, acyclovir, and lobucavir), BMS-200475 was most efficiently phosphorylated to the triphosphate in HepG2 cells.

* Corresponding author. Mailing address: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Pkwy. Wallingford, CT 06492-7660. Phone: (203) 677-6436. Fax: (203) 677-6088. E-mail: yamanaka{at}bms.com.

Antimicrobial Agents and Chemotherapy, January 1999, p. 190-193, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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