title: The octadecyloxyethyl ester of (S)-9-[3-hydroxy-2-(phosphonomethoxy) propyl]adenine is a potent and selective inhibitor of hepatitis C virus replication in genotype 1A, 1B, and 2A replicons.
abstract: The octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) esters of (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) are potent inhibitors of orthopoxvirus, herpesvirus, human immunodeficiency virus type 1, and hepatitis B virus replication in vitro. HDP and ODE esters of (S)-HPMPA and (R)-HPMPA were evaluated for their activity in hepatitis C virus (HCV) replicon assays using luciferase (1B and 2A replicons) or RNA (1B) quantification. The ODE ester of (S)-HPMPA [ODE-(S)-HPMPA] was the most active compound, with 50% effective concentrations (EC(50)s) in the 0.69 to 1.31 microM range. HDP and ODE esters of (R)-HPMPA were severalfold less active, while (S)-HPMPA and (R)-HPMPA were inactive. In genotype 1A and 1B replicons analyzed by HCV RNA analysis, ODE-(S)-HPMPA was the most active compound, with EC(50)s of 1.8 and 2.1 microM, respectively.
authors.affiliation: San Diego Veterans Medical Research Foundation and the Department of Medicine, Division of Infectious Disease, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0676, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Wyles
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Kaihara
authors.forename: Brent E
authors.initials: BE
authors.lastname: Korba
authors.forename: Robert T
authors.initials: RT
authors.lastname: Schooley
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D004952:Esters / Q000494:pharmacology; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D063065:Organophosphonates / Q000494:pharmacology*; D010957:Plasmids; D012093:Replicon; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004952:Esters; D063065:Organophosphonates; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine