Prodrug Strategies for the Development of β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU) against Varicella Zoster Virus (VZV)

Abstract

Varicella zoster virus (VZV) establishes lifelong infection after primary disease and can reactivate. Several drugs are approved to treat VZV diseases, but new antivirals with greater potency are needed. Previously, we identified), which had significant anti-VZV activity. In this communication, we report the synthesis and evaluation of numerous L-BHDU prodrugs: amino acid esters (14−26), phosphoramidates (33−34), long-chain lipids (ODE-L-BHDU-MP, 38, and HDP-L-BHDU-MP, 39), and phosphate ester prodrugs (POM-L-BHDU-MP, 41, and POC-L-BHDU-MP, 47). The amino acid ester L-BHDU prodrugs (L-phenylalanine, 16, and L-valine, 17) had a potent antiviral activity with EC 50 values of 0.028 and 0.030 μM, respectively. The phosphate ester prodrugs POM-L-BHDU-MP and POC-L-BHDU-MP had a significant anti-VZV activity with EC 50 values of 0.035 and 0.034 μM, respectively, and no cellular toxicity (CC 50 > 100 μM) was detected. Out of these prodrugs, ODE-L-BHDU-MP (38) and POM-L-BHDU-MP (41) were selected for further evaluation in future studies.

Enantioselective Synthesis of β-l-5-[(E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l-BHDU) via Chiral Pure l-Dioxolane

“… 26 Next, coupling of l -BHDU ( 17 ) was performed with POM chloride ( 23 ) in the presence of N -methyl imidazole in THF to furnish POM- l -BHDU-MP ( 24 ) in 55% yield ( Scheme 5 ). 16 …”

“…18 The pharmacokinetic studies revealed that POM- l -BHDU-MP had a better oral absorption profile compared to l -BHDU. 16 Repeated assay in humanized mice showed that POM- l -BHDU-MP was effective when administered orally once per day at 11.3 mg/kg or higher, which indicates its potency and bioavailability in vivo. 18 POM- l -BHDU-MP was evaluated as a topical treatment for VZV and HSV in a human skin explant model, which demonstrated highly effective antiviral activities against both viruses at 0.2% formulated in cocoa butter.…”

“…Recently, to increase the bioavailability and uptake of l -BHDU with enhanced pharmacokinetic properties, our group has developed the l -BHDU monophosphate pivaloyloxymethyl ester (POM- l -BHDU-MP) prodrug (Figure ). , POM- l -BHDU-MP has expressed antiviral activity similar to that of l -BHDU in infected cells. In contrast, POM- l -BHDU-MP was superior to l -BHDU in a VZV mouse model .…”

“…In contrast, POM- l -BHDU-MP was superior to l -BHDU in a VZV mouse model . The pharmacokinetic studies revealed that POM- l -BHDU-MP had a better oral absorption profile compared to l -BHDU . Repeated assay in humanized mice showed that POM- l -BHDU-MP was effective when administered orally once per day at 11.3 mg/kg or higher, which indicates its potency and bioavailability in vivo .…”

Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

“…These prodrugs are metabolized to their respective monophosphates by esterases, demonstrating an improved bioavailability. In recent studies, the improvement of the pharmacokinetic properties through the development of dipivoxil-and disoproxilmasked monophosphates was shown [112]. However, this type of prodrug has a significant drawback; upon their hydrolysis by esterases, the toxic formaldehyde is produced as a byproduct, making this approach less promising for further development [113].…”