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2V,3V-dideoxythymidine [D4T (stavudine)], have been reported to inhibit

HIV replication (for review, see Refs. [26 – 28]). In particular, FddClUrd

appears to be an attractive candidate for further development, since it is

much less toxic to the host cells than AZT and most other ddN analogues

[29,30]. Also ranking among the most promising ddN analogues are 3Vthia-2V,3V-dideoxycytidine [3TC (lamivudine)] and 3V-thia-2V,3V-dideoxy5-fluorocytidine (FTC), which are actually more active in their (– )-h- or

L-isomeric form than in the (+)-h- or D-isomeric form [31,32].

All ddN analogues, including 3TC and FTC, act in a similar fashion;

that is, following intracellular phosphorylation to their 5V-triphosphate

form, they serve as competitive inhibitors/alternate substrates of the reverse transcriptase (RT) reaction, thus leading to chain termination, as

has been clearly demonstrated with AZT [33]. The anti-HIV activity of

ddN analogues is critically dependent on their intracellular phosphorylation, the first phosphorylation step being the most crucial. For some

compounds (viz., 2V,3V-dideoxyuridine) and in some cells (viz., monocytes/macrophages), the nucleoside kinase activity of the cells may be

inadequate to satisfactorily accomplish the first phosphorylation step; and

thus prodrugs, including aryl methoxyglycinyl derivatives [34] and bis[S(2-hydroxyethylsulfidyl)-2-thioethyl] esters [35] have been designed that

deliver the 5V-monophosphate form intracellularly, bypassing the first

phosphorylation step.

The antiviral activity spectrum of the ddN analogues should, in

principle, extend to all retroviruses as well as hepadnaviruses [i.e., hepatitis B virus (HBV)], since HBV, like retroviruses, replicates through an

RNA template-driven RT process. Indeed, various ddN analogues (particularly, the L-enantiomeric forms 3TC, FTC, and L-DDC) have been

shown to inhibit HBV replication [36 –38]. Consequently, 3TC is, at present, pursued as a potential drug candidate for the treatment of both HIV

and HBV infections.

Prolonged AZT therapy of HIV-infected individuals leads to a reduction of virus sensitivity to the drug [39]. This reduced sensitivity, generally termed ‘‘resistance,’’ appears to be based on the following mutations

in the HIV-1 RT [40,41]: 41 Met ! Leu, 67 Asp ! Asn, 70 Lys ! Arg,

215 Thr ! Phe/Tyr, and 219 Lys ! Gln. Of these mutations, the

215 Thr ! Tyr mutation has been the most frequently detected among

AZT-resistant HIV isolates from patients under prolonged AZT therapy

[42]. The 74 Leu ! Val mutation is responsible for resistance to DDI [43],

and the 184 Met ! Val mutation confers resistance to 3TC, FTC, DDC,

and DDI [44 – 46].

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

The mutations at position 74 (Leu ! Val) and 184 (Met ! Val) of

the HIV-1 RT do not lead to cross-resistance to AZT. Nor would the 215

Thr ! Tyr mutation lead to cross-resistance to 3TC, FTC, DDC, or DDI.

In fact, the mutations at positions 74 and 215 seem to counteract each

other, and so do the mutations at positions 184 and 215. Based on this

‘‘mutually counteracting mutation’’ principle [47], drug combinations

could be envisaged that, if combined, might counteract emergence of resistance to one another: namely, combinations of AZT with either DDI,

3TC, FTC, or DDC. As will be explained further, these two-drug combinations may be extended to three-drug or four-drug combinations, following the addition of one or more of the HIV-1-specific nonnucleoside RT

inhibitors (NNRTIs).

B. Acyclic Nucleoside Phosphonates

Acyclic nucleoside phosphonates (ANPs) (Fig. 6) may be regarded as

analogous to the ddN monophosphates, thus allowing us to circumvent the

first phosphorylation step required for the intracellular activation of the

compounds. After they have been taken up as such by the cells, the acyclic nucleoside phosphonates (PMEA, PMEDAP, PMPA, PMPDAP,

FPMPA, and FPMPDAP) are converted intracellularly to their respective

diphosphate form (PMEApp, PMEDAPpp, PMPApp, PMPDAPpp,

FPMPApp, and FPMPDAPpp) and, in such form they interact as competitive inhibitors, alternate substrates, or chain terminators with the reverse transcriptase [48 –50].

PMEA and its congeners are more effective in vivo than could be

predicted from their in vitro potency. While less potent as an antiretrovirus agent than AZT in vitro, PMEA proved clearly superior to AZT

when the two drugs were compared for their effectiveness in vivo, in mice

infected with murine Moloney sarcoma virus [51,52]. PMEA was also

shown to be effective against various other retrovirus infections, including

Friend leukemia virus (FLV), Rauscher leukemia virus (RLV), and LPBM5 (murine AIDS) virus infection in mice, feline leukemia virus (FeLV)

or feline immunodeficiency virus (FIV) infection in cats, and SIV infection

in macaque (rhesus) monkeys (for review, see Ref. 53). In the latter model

[54], again PMEA proved far superior to AZT in suppressing several

parameters of the disease.

The antiviral activity spectrum of PMEA, PMEDAP, and their

congeners is not confined to retroviruses but also extends to hepadnaviruses (e.g., HBV). PMEA has proved effective against duck HBV infec-

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Figure 6 Acyclic nucleoside phosphonates (ANPs): 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) and -2,6-diaminopurine (PMEDAP), (R )-9-(2-phosphonylmethoxypropyl)-adenine (PMPA) and -2,6-diaminopurine (PMPDAP), (S )-9-(3fluoro-2-phosphonylmethoxypropyl)-adenine (FPMPA) and -2,6-diaminopurine

(FPMPDAP), and the bis(pivaloyloxymethyl) ester of PMEA [Bis(pom)-PMEA].

tion in both duck hepatocytes and Pekin ducks [55]. For PMEA and

PMEDAP, but not for PMPA, PMPDAP, FPMPA, or FPMPDAP, the

activity spectrum also extends to herpesviruses (e.g., HSV, CMV). This

would make PMEA and PMEDAP particularly attractive as therapeutic

modalities in AIDS patients, since they might be useful not only for the

treatment of the underlying HIV infection but also for the therapy/

prophylaxis of the intercurrent HSV or CMV infections.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Another attractive feature of PMEA, and, in fact, all ANPs, is

prolonged antiviral action, lasting for several days, or even one week or

longer, after a single-dose administration. This long-lasting antiviral

action may be related to the long half-life of the active metabolites (e.g.,

PMEApp) within the cells and may permit infrequent (e.g., weekly) dosing

of the ANPs in the prophylaxis and/or therapy of (retro)virus infections.

Little is known on how readily or rapidly retro- or herpesviruses may

develop resistance to the ANPs. In the in vitro and in vivo experiments

done so far with PMEA, PMEDAP, or any of the other ANPs, resistance

development did not seem to occur, but further studies are needed to

address this issue.

Since the ANPs are only slowly taken up by the cells and poorly

absorbed following oral administration, some efforts have been directed

toward the development of prodrugs (esters) that would be better taken up

by the cells. These efforts have yielded the bispivaloyloxymethyl [bis(pom)]

derivative of PMEA (Fig. 6) [56]. Bis(pom)-PMEA shows a cellular uptake increased more than a hundredfold, as well as fivefold better oral

bioavailability than the parent compound [57]. Both PMEA (given intravenously) and bis(pom)-PMEA (given perorally) are now in clinical trials

in patients with AIDS.





The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was

heralded by the discovery of the tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H )-one and -thione (TIBO) derivatives (Fig. 7) [58,59] and

1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives

(Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the

first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59]. For the

HEPT derivatives it became evident that they also interact specifically

with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and

E-EBU-dM) had been synthesized that were more active than HEPT

itself [62,63]. Following HEPT and TIBO, several other compounds, i.e.,

nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Figure 7 Tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H )-one (TIBO) derivatives (A) R82913 and (B) R86183 (with a chlorine substituted in the 9- or 8position, respectively).

Figure 8 (A) 1-(2-Hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT). (B) 5Isopropyl-1-(ethoxymethyl)-6-benzyluracil (I-EBU, MKC-442).

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

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