Agrofoglio LA, Mesplet N, Saito Y, Morin P; International Conference on AIDS.
Int Conf AIDS. 2002 Jul 7-12; 14: abstract no. TuPeB4540.
ICOA UMR CNRS 6005, Orleans, France
BACKGROUND: The 2',3'-dideoxynucleosides (ddNs) are among the most potent of nucleoside analogues active against human immunodeficiency virus in cell culture. Activation occurs via the intracellular conversion to the 5'-triphosphate, the kinase-mediated formation of the monophosphate being the rate limiting step and, therefore, the pro-drug strategies to deliver the monophosphate have been sought. In many respects, enantiomers have to be dealt with as different molecular entities. This applies in particular to the enaniomers of biologically active compounds like anti-HIV phosphoramidate prodrugs. Due to the asymmetric center at phosphorous, the actual non-stereoselective synthetic route produced the amidate prodrugs as a 1:1 mixture of two diastereomers. It has been shown for the PMPA pro-drug, GS-7340, that one of the diastereoisomers (on which the phosphorous chiral center was found to be S), was more potent and was identified as a candidate for clinical development. METHODS: As part of our drug discovery program, we have developed here an alternate method based on HPLC on chiral phase for the stereochemical separation of amidate pro-drug of some anti-HIV nucleosides. RESULTS: Structural and chromatographic data for several diastereomeric NRTIs will be given. A baseline separation could be achieved within less than 10 minutes. Studies of the stability of those diastereomers in plasma or within an esterase as well as MS studies will be presented. CONCLUSION: This method would be usefull to assess the pharmacokinetics and mechanism of action, as well as, the unknown biological activity of some individual pro-drugs of NRTIs. This work was supported in part by the Agence Nationale de Recherche sur le SIDA (ANRS) and by Ensemble Contre le SIDA (ECS).
Publication Types:
Keywords:
- Adenine
- Amides
- Antiviral Agents
- Chromatography, High Pressure Liquid
- Dideoxynucleosides
- Esterases
- GS-7340
- Humans
- Nucleosides
- Nucleotides
- Pharmaceutical Preparations
- Phosphonic Acids
- Phosphoric Acids
- Prodrugs
- Proline
- Stereoisomerism
- phosphoramidic acid
- tenofovir
Other ID:
UI: 102250045
From Meeting Abstracts