Amino Acid Ester Prodrugs of Nucleoside and Nucleotide Antivirals
Language English Country Netherlands Media print
Document type Journal Article, Review
PubMed
28215138
DOI
10.2174/1389557517666170216151601
PII: MRMC-EPUB-81827
Knihovny.cz E-resources
- Keywords
- Acyclic nucleoside analogues, antiherpetics, antiretrovirals, cidofovir, peptidomimetics, prodrugs, tyrosine esters, valacyclovir,
- MeSH
- Adenine analogs & derivatives chemistry pharmacology MeSH
- Antiviral Agents chemistry pharmacology MeSH
- Cidofovir MeSH
- Cytomegalovirus drug effects MeSH
- Cytosine analogs & derivatives chemistry pharmacology MeSH
- Humans MeSH
- Nucleosides chemistry pharmacology MeSH
- Nucleotides chemistry pharmacology MeSH
- Organophosphonates chemistry pharmacology MeSH
- Prodrugs chemistry pharmacology MeSH
- Herpesvirus 3, Human drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- adefovir MeSH Browser
- Adenine MeSH
- Antiviral Agents MeSH
- Cidofovir MeSH
- Cytosine MeSH
- Nucleosides MeSH
- Nucleotides MeSH
- Organophosphonates MeSH
- Prodrugs MeSH
OBJECTIVE: The review covers basic principles of the prodrug strategy applied to antiviral nucleoside drugs or drug candidates. Specific role of amino acids as promoieties is explained with respect to transport mechanisms, pharmacokinetics and a low toxicity of compounds. Synthetic approaches to the most important representatives (compounds under clinical investigations or available on the market) are described, including valacyclovir, valganciclovir, valomaciclovir stearate, valcyclopropavir, valtorcitabine, valopicitabine and several attempts to amino acid modifications of antiretroviral nucleosides. METHOD: A special attention is paid to acyclic nucleoside phosphonates, where the phosphonic acid residue is esterified with a side-chain hydroxyl group of appropriate amino acid (serine, tyrosine) which can be used as single amino acid or as a part of dipeptides further modified on the terminal carboxyl function. The most advantageous pharmacokinetic profile and the best oral bioavailability were found in tyrosinebased prodrugs. RESULTS & CONCLUSION: Studies were performed successfully on 1-(S)-[3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (cidofovir), 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine and some (R)-2- (phosphonomethoxy)propyl and 2-(phosphonomethoxy)ethyl derivatives including adefovir.
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