Prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T): synthesis, antiviral activity, and rapid pharmacokinetic evaluation
| Autor: | D R, Tortolani, J W, Russell, V J, Whiterock, M J, Hitchcock, I, Ghazzouli, J C, Martin, M M, Mansuri, J E, Starrett |
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| Rok vydání: | 1994 |
| Předmět: |
Chemical Phenomena
Chemistry Stereochemistry Chemistry Physical Stavudine Dihydropyridine Pharmaceutical Science Biological Availability HIV Prodrug Chemical synthesis Antiviral Agents Bioavailability Leukemia Virus Murine Pyrimidine analogue Mice Pharmacokinetics Oral administration parasitic diseases medicine Animals Prodrugs medicine.drug |
| Zdroj: | Journal of pharmaceutical sciences. 83(3) |
| ISSN: | 0022-3549 |
| Popis: | 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 bioavailabillty 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. |
| Databáze: | OpenAIRE |
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