Evolution of an Amino Acid Based Prodrug Approach: Stay Tuned

Abstract

Certain acyclic nucleoside phosphonates (ANPs) such as (S)-HPMPC (cidofovir, Vistide®) and (S)-HPMPA have been shown to be active against a broad spectrum of DNA and retroviruses. However, their poor absorption as well as their toxicity limit the utilization of these therapeutics in the clinic. Nucleoside phosphonates are poorly absorbed primarily due to the presence of the phosphonic acid group, which ionizes at physiological pH. When dosed intravenously they display dose-limiting nephrotoxicity due to their accumulation in the kidney. To overcome these limitations, nucleoside phosphonate prodrug strategies have taken center stage in the development pathway and a number of different approaches are at various stages of development. Our efforts have focused on the development of ANP prodrugs in which a benign amino acid promoiety masks a phosphonate P-OH via a hydroxyl side chain. The design of these prodrugs incorporates multiple chemical groups (the P−X−C linkage, the amino acid stereochemistry, the C-terminal and N-terminal functional groups) that can be been tuned to modify absorption, pharmacokinetic and efficacy properties with the goal of improving overall prodrug performance.

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…For example, cidofovir ( 53 ) can be converted to a cyclic monoester (cyclic cidofovir, 54 ) which in turn can be further modified at the remaining acid function (reviewed by Krylov [102]). As a prodrug, the cyclic cidofovir 54 offers advantages over the parent compound in that only one ionizable function remains, and hydrolysis to the parent drug does not release any additional products.…”

Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals

“…These prodrug forms such as phosphoramidates and cyclo Sal-phosphate triesters of nucleoside analogues were indeed shown to deliver the NMP either by chemical or enzymatic hydrolysis in the target cells 22 23 24 25 26 27 . In addition to NMPs also the successful delivery of acyclic nucleoside phosphonates such as cidofovir has been reported 28 . However, all these approaches delivered the monophosphor(n)ylated forms of the nucleosides that subsequently needed further phosphorylation into the triphosphate forms by cellular kinases to inhibit their target polymerase.…”

Phase I trial evaluating the antiviral agent Cidofovir in combination with chemoradiation in cervical cancer patients

“…Cidofovir has also demonstrated antitumor activity in other malignancies such as glioblastomas [ 29 ]. Improved pharmacological versions (including nanotechnology) of cidofovir are becoming available and will increase the efficacy/tolerance ratio [ 30 , 31 ]. Another phase I/II with such antiviral compounds will shortly be initiated in our institution for patients with locally advanced cervical cancer.…”