title: Marked inhibitory activity of masked aryloxy aminoacyl phosphoramidate derivatives of dideoxynucleoside analogues against visna virus infection.
abstract: Lipophilic masked aryloxyaminoacylphosphoramidate derivatives of 2',3'-dideoxynucleoside (ddN) analogues with potent anti-HIV activity (i.e., stavudine [d4T], azidothymidine [AZT], dideoxycytidine [ddC], 3'thio-2',3'-dideoxy cytidine [3TC], dideoxyadenosine [ddA], and 2',3'-didehydro-2',3'-dideoxyadenosine [d4A]) activity were evaluated for their activity against visna virus (VV) in sheep choroid plexus (SCP) cells. The activity of several prodrug derivatives against VV proved markedly superior to that of the corresponding free ddN analogues. In particular, the d4A and ddA prodrug derivatives were exquisitely inhibitory in this model system (50% effective concentration [EC50], < or = 0.003 microM), and their anti-VV potency exceeded by at least 200-fold the antiviral potency of the corresponding free nucleosides. Marked differences were noted in the anti-VV potencies of several of the test compounds depending on the nature of the amino acid linked to the 5'-phosphate moiety, the nature of the nucleoside, or both. In view of the stability of the prodrugs in lamb serum, the VV infection model in lambs may be considered highly useful for investigating the in vivo antiretroviral efficacy of these type of drugs, particularly the d4T, ddA, and d4A prodrug derivatives.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: D
authors.initials: D
authors.lastname: Cahard
authors.forename: O
authors.initials: O
authors.lastname: Wedgwood
authors.forename: A
authors.initials: A
authors.lastname: Salgado
authors.forename: S
authors.initials: S
authors.lastname: Velázquez
authors.forename: C J
authors.initials: CJ
authors.lastname: Yarnold
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: C
authors.initials: C
authors.lastname: McGuigan
authors.forename: H
authors.initials: H
authors.lastname: Thormar
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002831:Choroid Plexus / Q000166:cytology / Q000187:drug effects / Q000821:virology; D015224:Dideoxynucleosides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004355:Drug Stability; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D012756:Sheep; D014779:Virus Replication / Q000187:drug effects; D014790:Visna-maedi virus / Q000187:drug effects* / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D015224:Dideoxynucleosides; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase