title: Prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T): synthesis, antiviral activity, and rapid pharmacokinetic evaluation.
abstract: A series of 5'-derivatives and modified pyrimidine analogues of 2',3'-didehydro-3'-deoxythymidine (d4T, stavudine, 1) were synthesized to determine their potential as oral prodrugs of d4T. Utilizing a screen developed for the rapid evaluation of a variety of prodrugs in mice, it was determined that 5'-acetate 2 provided comparable plasma levels of d4T after oral administration of the prodrug to that when d4T was administered alone. The relative oral bioavailability of methoxy acetate 3 and cyclohexyl carbonate 5 was 79 and 41%, respectively. Dihydropyridine ester 6 did not provide detectable levels of d4T up to 1 h after oral administration of 6. Thiopyrimidines 8 and 9, as well as aminopyrimidine 10 also failed to provide measurable levels of d4T after oral administration. 5'-Derivatives 3, 5, and 6 showed similar activity to that of d4T against HIV and MuLV, as did 5'-benzoyl-4-thio derivative 8. However, the corresponding 4-thio 5'-alcohol 9 was inactive.
authors.affiliation: Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, CT 06492-7660.
authors.forename: D R
authors.initials: DR
authors.lastname: Tortolani
authors.forename: J W
authors.initials: JW
authors.lastname: Russell
authors.forename: V J
authors.initials: VJ
authors.lastname: Whiterock
authors.forename: M J
authors.initials: MJ
authors.lastname: Hitchcock
authors.forename: I
authors.initials: I
authors.lastname: Ghazzouli
authors.forename: J C
authors.initials: JC
authors.lastname: Martin
authors.forename: M M
authors.initials: MM
authors.lastname: Mansuri
authors.forename: J E
authors.initials: JE
authors.lastname: Starrett
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006678:HIV / Q000187:drug effects; D009052:Leukemia Virus, Murine / Q000187:drug effects; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018119:Stavudine / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D018119:Stavudine