title: Tyrosine-based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodrugs: synthesis, stability, antiviral activity, and in vivo transport studies.
abstract: Eight novel single amino acid (6-11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPC, 4) and its cyclic adenine analogue ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC(50) values for the prodrugs (<0.1-50 μM) vs vaccinia, cowpox, human cytomegalovirus, and herpes simplex type 1 virus were compared to those for the parent drugs ((S)-HPMPC, 2; (S)-HPMPA, 1; IC(50) 0.3-35 μM); there was no cytoxicity with KB or HFF cells at ≤100 μM. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30-1732 min) with differences of 3-10× between phostonate diastereomers. The tyrosine alkylamide derivatives of 3 and 4 were the most stable. (l)-Tyr-NH-i-Bu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39% vs <5%).
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA.
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Zakharova
authors.forename: Michaela
authors.initials: M
authors.lastname: Serpi
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Krylov
authors.forename: Larryn W
authors.initials: LW
authors.lastname: Peterson
authors.forename: Julie M
authors.initials: JM
authors.lastname: Breitenbach
authors.forename: Katherine Z
authors.initials: KZ
authors.lastname: Borysko
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Mindy
authors.initials: M
authors.lastname: Collins
authors.forename: John M
authors.initials: JM
authors.lastname: Hilfinger
authors.forename: Boris A
authors.initials: BA
authors.lastname: Kashemirov
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000077404:Cidofovir; D015608:Cowpox virus / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D014443:Tyrosine / Q000737:chemistry*; D014616:Vaccinia virus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; D014443:Tyrosine; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D000077404:Cidofovir