Prodrugs of phosphonates and phosphates: crossing the membrane barrier

Abstract

A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well, but small charged molecules can have difficulty traversing the cell membrane by means other than endocytosis. The resulting dichotomy has stimulated a great deal of effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes, but able to release the parent drug once inside the target cell. This chapter presents recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

Fig. 1

General structures of the phosphate and phosphonate groups

Fig. 2

General structures of phosph(on)ate prodrugs

Fig. 3

Use of phosphates to enhance water solubility of drugs

Fig. 4

Examples of pivaloyloxymethyl (POM)-modified drugs

Fig. 5

Tenofovir disoproxil, an isopropyloxycarbonyloxymethyl (POC)-modified drug

Fig. 6

S-acylthioalkyl ester (SATE) modified nucleoside analogues.

Fig. 7

CycloSal-PMEA (37) and some nonracemic cycloSal derivatives

Fig. 8

The HepDirect strategy for phosph(on)ate prodrugs

Fig. 9

Prodrugs derived from phosph(on)ate di(or mono) esters

Fig. 10

Prodrugs including internal ester formation

Fig. 11

A phosphate prodrug including internal esterification

Fig. 12

Phosphate and phosphonate prodrugs based on symmetrical di-amidates

Fig. 13

Aryl phosphoramidate prodrugs

Fig. 14

Alkyl phosphoramidate prodrugs

Fig. 15

Mono phosphoramidate prodrugs

Fig. 16

Drug release from diamidates and aryloxy amidates [120]

Fig. 17

A diphosphate prodrug

Fig. 18

Prodrugs assayed as the S_P isomers

Fig. 19

Prodrugs of some purine biosynthesis inhibitors

Fig. 20

Examples of first generation bisphosphonates and a prodrug form

Fig. 21

Prodrugs of farnesyl diphosphate synthase and geranylgeranyl di-phosphate synthase

Fig. 22

Monophosphate prodrugs that inhibit prenyl transferases.

Fig. 23

Fosmidomycin and prodrug analogues

Fig. 24

Bis-POM prodrug of an SH2 targeted peptidomimetic

Fig. 25

Aryl phosphoramidate peptidomimetics

Fig. 26

Some prodrug forms used in peptidomimetics

Scheme 1

The products of POM, POC, and SATE prodrug cleavage

Scheme 2

The products of HepDirect prodrug cleavage