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Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.

Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.
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Luo M, Groaz E, Andrei G, Snoeck R, Kalkeri R, Ptak RG, Hartman T, Buckheit RW, Schols D, De Jonghe S, Herdewijn P,


Luo M, Groaz E, Andrei G, Snoeck R, Kalkeri R, Ptak RG, Hartman T, Buckheit RW, Schols D, De Jonghe S, Herdewijn P, (click to view)

Luo M, Groaz E, Andrei G, Snoeck R, Kalkeri R, Ptak RG, Hartman T, Buckheit RW, Schols D, De Jonghe S, Herdewijn P,

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Journal of medicinal chemistry 2017 07 0660(14) 6220-6238 doi 10.1021/acs.jmedchem.7b00416

Abstract

Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.

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