The ProTide Prodrug Technology: From the Concept to the Clinic

Abstract

The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this approach, the hydroxyls of the monophosphate or monophosphonate groups are masked by an aromatic group and an amino acid ester moiety, which are enzymatically cleaved-off inside cells to release the free nucleoside monophosphate and monophosphonate species. Structurally, this represents the current end-point of an extensive medicinal chemistry endeavor that spans almost three decades. It started from the masking of nucleoside monophosphate and monophosphonate groups by simple alkyl groups and evolved into the sophisticated ProTide system as known today. This technology has been extensively employed in drug discovery, and it has already led to the discovery of two FDA-approved (antiviral) ProTides. In this work, we will review the development of the ProTide technology, its application in drug discovery, and its role in the improvement of drug delivery and efficacy.

Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

“…To overcome these challenges, a number of monophosphate prodrug approaches have been developed, and these have been used widely in the discovery of nucleotide‐based therapeutics . Among the most successful monophosphate prodrug approaches is the ProTide technology, which has delivered more than ten clinical candidates and two FDA‐approved drugs . In this prodrug approach, the monophosphate group is masked by an aryl group and an amino acid ester to generate a prodrug that is neutral at physiological pH and is passively taken up by cells (Scheme B) .…”

“…Among the most successful monophosphate prodrug approaches is the ProTide technology, which has delivered more than ten clinical candidates and two FDA‐approved drugs . In this prodrug approach, the monophosphate group is masked by an aryl group and an amino acid ester to generate a prodrug that is neutral at physiological pH and is passively taken up by cells (Scheme B) . Upon cell entry, the masking groups are enzymatically cleaved off to release the nucleoside analogue monophosphate, which could then be further phosphorylated by cellular nucleotide kinases to give the active triphosphate species (Scheme B) …”

Synthesis of fluorinated acyclic nucleoside phosphonates with 5-azacytosine base moiety

“…The most frequently used ANP prodrugs are acyloxyalkyl (pivaloyloxymethyl, POM), alkyloxyalkyl, S-acylthioethyl (SATE), aryl, cyclic 1aryl-1,3-propanyl and cyclosaligenyl phophonate esters, phosphoramidates bearing amino acid esters and proTides [19]. The usual way to overcome this problem is the transformation of such compounds to appropriate prodrugs.…”

“…31 P { 1 H} NMR spectra were recorded on Bruker Avance 500 III HD or Bruker Avance 400 III HD operating at 202.3 or 162.0 MHz, respectively 19. Compound 13 was purified on a column (3.3 Â 1.7 cm) of spherical reverse phase silica gel C18 (45e75 mm), 70 Å (Versa Flash, Supelco), (S8).…”

Synthesis and Antiviral Evaluation of TriPPPro‐AbacavirTP, TriPPPro‐CarbovirTP, and Their 1′,2′‐cis‐Disubstituted Analogues

“…Until recently the standard of care was ac ombination of ribavirin and PEGylated interferon-a (IFN-a), but this is limited tõ 50 %o fp atients due to toxic side effects and the ineffectiveness of the therapy to various viral genotypes. [10] To bypass metabolic hurdles in phosphorylation, nucleotide prodrugs have been introduced (e.g.,p hosphoramidates, [11] cycloSal [12] and DiPPro compounds [13] ). [6][7][8] The mode of action of all these nucleo(s/t)ides is inhibition of the viral replication catalyzed by RNA or DNA polymerases.…”