title: Antiviral efficacy upon administration of a HepDirect prodrug of 2'-C-methylcytidine to hepatitis C virus-infected chimpanzees.
abstract: Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide, and the current standard of care, a combination of pegylated interferon alpha and ribavirin, is efficacious in achieving sustained viral response in ~50% of treated patients. Novel therapies under investigation include the use of nucleoside analog inhibitors of the viral RNA-dependent RNA polymerase. NM283, a 3'-valyl ester prodrug of 2'-C-methylcytidine, has demonstrated antiviral efficacy in HCV-infected patients (N. Afdhal et al., J. Hepatol. 46[Suppl. 1]:S5, 2007; N. Afdhal et al., J. Hepatol. 44[Suppl. 2]:S19, 2006). One approach to increase the antiviral efficacy of 2'-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5'-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2'-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ~1.4 log(10) IU/ml and by >3.6 log(10) IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA. steve_carroll@merck.com
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.forename: Kenneth
authors.initials: K
authors.lastname: Koeplinger
authors.forename: Marissa
authors.initials: M
authors.lastname: Vavrek
authors.forename: Nanyan Rena
authors.initials: NR
authors.lastname: Zhang
authors.forename: Laurence
authors.initials: L
authors.lastname: Handt
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.forename: Zhili
authors.initials: Z
authors.lastname: Sun
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Poelje
authors.forename: James M
authors.initials: JM
authors.lastname: Fujitaki
authors.forename: Serge H
authors.initials: SH
authors.lastname: Boyer
authors.forename: David L
authors.initials: DL
authors.lastname: Linemeyer
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hecker
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003562:Cytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003568:Cytidine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D002679:Pan troglodytes; D011355:Prodrugs / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D011741:Pyrimidine Nucleosides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D011741:Pyrimidine Nucleosides; C513402:2'-C-methylcytidine; D003562:Cytidine; D003568:Cytidine Monophosphate; C506207:valopicitabine