Amino Acid Ester Prodrugs of Nucleoside and Nucleotide Antivirals

Title:Amino Acid Ester Prodrugs of Nucleoside and Nucleotide Antivirals

Volume: 17 Issue: 10

Author(s): Marcela Krečmerová*

Affiliation:

• Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6,Czech Republic

Keywords: Acyclic nucleoside analogues, antiherpetics, antiretrovirals, cidofovir, peptidomimetics, prodrugs, tyrosine esters, valacyclovir.

Abstract: 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.

Cite this article as:

Krečmerová Marcela *, Amino Acid Ester Prodrugs of Nucleoside and Nucleotide Antivirals, Mini-Reviews in Medicinal Chemistry 2017; 17 (10) . https://dx.doi.org/10.2174/1389557517666170216151601