title: Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates.
abstract: Bis(pivaloyloxymethyl) [bis(pom)] derivatives of various acyclic nucleoside phosphonates--9-(2-phosphonylmethoxyethyl)adenine (PMEA), 9-(2-phosphonylmethoxypropyl)adenine (PMPA), and 9-(2-phosphonylmethoxypropyl)diaminopurine (PMPDAP)--were found to exhibit 9- to 23-fold greater antiviral activity than their corresponding unmodified compounds. The cytotoxicity of the bis(pom) analogs was also increased by various degrees, thus altering the therapeutic indexes of these compounds. Metabolic studies using [3H]bis(pom)PMEA and [3H]PMEA as model compounds suggested a > 100-fold increase in the cellular uptake of the bis(pom) derivative and formation of active diphosphorylated metabolite. However, the bis(pom) derivatives were chemically unstable and highly susceptible to serum-mediated hydrolysis, factors which limit their potential utility for intracellular drug delivery.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: R V
authors.initials: RV
authors.lastname: Srinivas
authors.forename: B L
authors.initials: BL
authors.lastname: Robbins
authors.forename: M C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Y F
authors.initials: YF
authors.lastname: Gong
authors.forename: N
authors.initials: N
authors.lastname: Bischofberger
authors.forename: A
authors.initials: A
authors.lastname: Fridland
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008221:Lymphoid Tissue / Q000166:cytology; D009705:Nucleosides / Q000378:metabolism* / Q000494:pharmacology*; D063065:Organophosphonates / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D063065:Organophosphonates; D011355:Prodrugs; C053001:adefovir; D000225:Adenine