Anti-Human Immunodeficiency Virus Activity and Cellular Metabolism of a Potential Prodrug of the Acyclic Nucleoside Phosphonate 9- R -(2-Phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA

Abstract

Bis(isopropyloxymethylcarbonyl) 9-R-(2-phosphonomethoxypropyl)adenine [bis(POC)PMPA] has been identified as a novel prodrug of PMPA. The anti-human immunodeficiency virus activity of bis(POC)PMPA was >100-fold greater than that of PMPA in both an established T-cell line and primary peripheral blood lymphocytes. This improved efficacy was shown to be due to a rapid intracellular uptake of the prodrug resulting in an increased intracellular accumulation of PMPA diphosphate (PMPApp), the pharmacologically active metabolite. PMPApp levels in bis(POC)PMPA-treated cells exceeded by >1,000-fold the levels seen in cells treated with unmodified PMPA in both resting and activated peripheral blood lymphocytes. Significant differences in the intracellular catabolism of PMPA metabolites were noted between the resting and activated lymphocytes. The half-life for the disappearance of PMPApp, derived from either bis(POC)PMPA or PMPA, was 12 to 15 h in the activated lymphocytes and 33 to 50 h in the resting lymphocytes. This long persistence of PMPApp, particularly in resting lymphocytes, may be unique to the nucleoside phosphonate analogs and indicates that effective levels of the active metabolite can be achieved and maintained with relatively infrequent administration of the parent drug.

Synthesis And Anti-Hiv Activity Of Cyclic Pyrimidine Phosphonomethoxy Nucleosides And Their Prodrugs: A Comparison Of Phosphonates And Corresponding Nucleosides

“…Improvements in potency also were found for the corresponding bisPOC prodrug of d4U phosphonate (5) thereby indicating that this prodrug strategy is broadly applicable toward improving the antiviral potency of cyclic phosphonates, similar to that observed for Viread (1). [3] It is noteworthy that the antiviral activity of bisPOC d4T phosphonate is now several-fold improved over nucleoside d4T despite being a weaker inhibitor of RT. It, therefore, is likely that higher levels of active metabolites are generated by d4T phosphonate (2) through superior metabolism properties and a longer intracellular half-life of the active species.…”

“…It, therefore, is likely that higher levels of active metabolites are generated by d4T phosphonate (2) through superior metabolism properties and a longer intracellular half-life of the active species. [3] The resistance profile of bisPOC (2) toward viruses containing six thymidine analog mutations (6TAMs), K65R or M184V was evaluated and compared to d4T (Table 2). A comparable resistance profile was observed toward the M184V and 6TAMs, whereas a small increase was observed in the K65R resistance.…”

Tenofovir and Adefovir as Antiviral Agents

“…One important general aspect of the metabolism of ANPs is the intracellular persistence of their active diphosphate metabolites. The intracellular half-lives of adefovir and tenofovir diphosphates in T cells are approximately 16 h [44] and 21 h [4], respectively, which compares favorably with the shorter half-lives of active triphosphates of nucleoside analogues [46]. The efficient conversion of adefovir and tenofovir into their respective diphosphates in hepatic cells (HepG2 or primary hepatocytes) has also been confirmed [47,48].…”

“…In cellbased assays, TDF and ADV are 20-to 100-fold more potent against HIV-1 compared to their respective parent nucleotides [4,82,83]. Similarly, the potency of adefovir and tenofovir against HBV in cell culture models increases by 10-and 100-fold, respectively, after their conversion to the dialkoxyester prodrugs (Table 24.2) [48].…”

Cytosine deoxyribonucleoside anti-HIV analogues: a small chemical substitution allows relevant activities

“…Given that the TDF diphosphate half-life was 10-50 h in stimulated and resting PBMCs [51], TDF and FTC metabolites exhibit long and comparable intracellular decay times.…”