title: Synthesis and biological properties of prodrugs of (S)-3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid.
abstract: The lack of antiviral activity of recently described (S)-3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid, or (S)-CPMEA in brief, has been speculated to possibly be due to the increased hydrophilicity of the molecule and, thus, by its limited cellular permeability. Efficient syntheses of novel lipophilic prodrugs of (S)-CPMEA masking either the carboxylic group or preferably both the phosphonate and carboxylic moieties, have been developed in order to increase bioavailability of the parent compound. Two prodrugs of (S)-CPMEA, namely phosphonate bis-amidate 15 and phenyloxy amidate 16, exhibited pan-genotypic anti-HCV activity at submicromolar concentrations.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, CZ-16610, Prague 6, Czech Republic.
authors.forename: Martin Maxmilian
authors.initials: MM
authors.lastname: Kaiser
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, CZ-16610, Prague 6, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Poštová-Slavětínská
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, CZ-16610, Prague 6, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Dračínský
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, 94404, USA.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, 94404, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, CZ-16610, Prague 6, Czech Republic. Electronic address: janeba@uochb.cas.cz.
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Janeba
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; C000611424:diethyl 2,2'-(((((3-(adenin-9-yl)-1-methoxy-1-oxopropan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))bis(2-phenylpropanoate); C000611425:ethyl 3-(adenin-9-yl)-2-((((2-ethoxy-2-oxo-1-phenylethyl)amino)(phenoxy)phosphoryl)methoxy)propanoate; D000225:Adenine
keywords: (S)-CPMEA; Acyclic nucleoside phosphonates; Antiviral; HCV; Prodrugs