DISCOVERY AND DEVELOPMENT OF NEW ANTIVIRALS FOR SMALLPOX in .NET

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DISCOVERY AND DEVELOPMENT OF NEW ANTIVIRALS FOR SMALLPOX
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does not exist, the emphasis has been on identifying antiviral agents that are already approved for another indication. One such compound, cidofovir (CDV), is approved for intravenous use in the treatment of cytomegalovirus (CMV) retinitis in HIVinfected patients. The drug is very active in tissue culture cells against all the orthopoxviruses that have been tested including vaccinia, cowpox, monkeypox, and variola viruses.14,15,18 21 The activity of CDV against orthopoxviruses is of particular interest since the compound has been shown to be active in animal models infected with vaccinia virus (VV) and cowpox virus (CV).16,19,22 26 Importantly, it has recently been reported to be highly effective in treating monkeys infected with variola or monkeypox viruses.27 Although CDV is a highly effective inhibitor of orthopoxvirus replication, it is absorbed poorly when administered orally.28,29 The lack of oral bioavailability is a major limitation to the use of this drug in a large-scale emergency situation such as a smallpox outbreak. While this does not preclude the use of CDV under those conditions, and the drug is approved for use in the treatment of smallpox and complications of vaccination, it does present some challenging logistical problems. Its toxicity and lack of oral activity provide a rationale for the discovery and development of new orally active chemotherapeutic agents for treatment and/or prevention of orthopoxvirus infections whether acquired in a natural setting or through bioterrorism activities. There are a number of issues that should be considered in the development of a drug for use in a situation such as smallpox when the target population includes all members of society including children and immunocompromised patients. In addition to being active orally, the drug should have a long intracellular half-life so administration can be infrequent and of course have a toxicity pro le that is acceptable for all individuals. Additionally, since the drug will need to be stockpiled for a future potential need, it needs to be inexpensive and highly stable under a variety of storage conditions. The purpose of this chapter is to review recent progress in the development of new agents or modi cation of existing compounds such as CDV for orthopoxvirus infections. The chapter is organized somewhat into nucleoside analogues, cidofovir, nucleoside phosphonate analogues, and the ether lipid ester prodrugs of cidofovir.
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NUCLEOSIDE ANALOGUES
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There are numerous nucleoside analogues that have been reported to have antiviral activity against VV.18 Since there is little incentive to develop a new drug for use in orthopoxvirus infection, we have evaluated most of the antiviral drugs for their activity against VV and CV that have been either licensed for use for some other indication or have been through advanced clinical studies.30 Those drugs with signi cant poxvirus activity are listed in Table 14.1 and include drugs approved primarily for herpesvirus or human immunode ciency virus (HIV) infections. For
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NUCLEOSIDE ANALOGUES
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TABLE 14.1 Activity of Nucleoside Analogues Against Vaccinia and Cowpox Viruses in HFF Cells Cytotoxicity CC50 (mM) >317 >260 >338 >351 >269 117 Vaccinia Copenhagen EC50(mM) SI 31 5.4 6.0 0.2 1.7 12 1.5 0.05 5.1 0.7 >10 >43 >199 >29 >179 23 Cowpox Brighton EC50 (mM) SI 42 5.4 2.0 0.2 1.5 45 0.2 0.08 13 8.8 >7.5 >130 >225 >8 >1345 9.0
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Compound Cidofovir Idoxuridine Tri uridine Vidarabine Fialuridine Adefovir dipivoxil
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Source: Adapted from Kern.30
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the HIV inhibitors, we tested representative compounds for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. The compounds that exhibited the greatest activity against the two poxviruses were CDV, idoxuridine, tri uridine, vidarabine, aluridine, and adefovir dipivoxil. As mentioned previously, CDV is the most promising candidate on this list. Although long-term administration results in signi cant nephrotoxicity,31 its use for a smallpox outbreak would be infrequent and short-term and, under these conditions, its toxicity may not be an issue;32 however its need for parenteral administration remains a logistical limitation. Idoxuridine and tri uridine, which are both approved for topical treatment of herpes simplex virus (HSV) keratitis, do not have a suf cient toxicology database to support parenteral use. Vidarabine, the rst parenteral therapy approved for serious herpesvirus infections, is not active orally and was not very active in murine models for VV or CV infections (E.R. Kern, unpublished data).33 The results also indicated that adefovir dipivoxil and aluridine were active candidates. Although aluridine is very active in tissue culture, its lack of activity in mouse models of VV33 and its previous toxicity history in treatment of hepatitis in humans probably precludes it as a serious candidate. Adefovir dipivoxil, on the other hand, does appear to be a serious candidate in that it is very active against VV and CV replication in tissue culture, has good oral bioavailability,34 and has been approved for treatment of hepatitis B. It needs to be evaluated against monkeypox virus and variola virus before its real potential is known. The instability of the compound in mouse plasma has prevented demonstration of activity in VV- or CVinfected mice (E.R. Kern, unpublished data). Another nucleoside analogue, 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl] purine (S2242), and its orally active prodrug (HOE961) have been reported to be very active against VV and CV in tissue culture and in experimental animal model infections.35,36 Although these compounds have potential for use in treating orthopoxvirus infections in humans, no clinical studies have been reported.
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