DISCOVERY AND DEVELOPMENT OF NEW ANTIVIRALS FOR SMALLPOX in .NET framework

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DISCOVERY AND DEVELOPMENT OF NEW ANTIVIRALS FOR SMALLPOX
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mortality from CV infections. Our studies con rm these observations and further indicate that viral replication is signi cantly reduced in target organs of SCID mice while on treatment. Our results with CV mirror those of Neyts and De Clercq,19 who reported reduced viral titers in lung, kidney, and liver of VV-infected SCID mice treated with CDV. The most appropriate animal model for studying smallpox and monkeypox infections is nonhuman primates inoculated with either variola or monkeypox viruses. In these two experimental infections, cidofovir was highly effective in reducing viral replication and lesion development.27 Collectively, these data indicate that CDV is able to signi cantly reduce mortality in mice exposed to VV or CV when given as late as 96 h postinoculation. For protection from death, CDV can be reduced to one single dose or one to three smaller doses. Protection from infection can also be conferred by pretreatment with CDV as early as 5 days prior to exposure. The results obtained for SCID mice suggest that long-term treatments may be necessary for protecting immunocompromised individuals. These collective results have major implications, as they suggest that CDV, in addition to being effective as a treatment for smallpox or vaccine complications, can be used for pre- or postexposure prophylaxis of smallpox contacts (i.e., ring treatment) and that a single dose may provide signi cant protection. From these data it is clear that the effect of CDV is long lasting and may translate to short-term or single-dose treatment for smallpox or other orthopoxvirus infections. 14.4 ACYCLIC NUCLEOSIDE PHOSPHONATE ANALOGUES
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Since CDV is one of the few well-characterized compounds with good activity against the orthopoxviruses, we have also evaluated a large number of other acyclic nucleoside phosphonates for their activity against VV and CV replication in vitro, and the results are presented in Table 14.5. A number of these compounds have been described previously by De Clercq and his colleagues and are reviewed by
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TABLE 14.5 Ef cacy and Cytotoxicity of Phosphonate Nucleotides Against Vaccinia and Cowpox Viruses in HFF Cells Cytotoxicity CC50 (mM) Vaccinia Virus EC50 (mM) SIa 33 9.1 38 11 3.5 2.8 >366 0 204 15 >300 4.0 0.7 8 >8 77 22 Cowpox Virus EC50 (mM) SI 43 2.5 48 8.0 5.0 4.7 >366 0 >347 0 >300 11.4 1.3 7 >6 54 8
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Compound
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HPMPC (CDV) 278 9.2 Cyclic HPMPC (cHPMPC) >302 0 S-HPMPA 269 21 PMEA >366 0 PMEDAP >339 12 PMPA >300 PMEG 88
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SI CC50/EC50. Source: Adapted from Kern.30
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ACYCLIC NUCLEOSIDE PHOSPHONATE ANALOGUES
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De Clercq.18 In the CDV series, there are a number of prodrugs that have equal or greater activity against VV and CV than CDV; however, little is known about their toxicity or pharmacokinetics at the present time. The adenine analogue S-HPMPA [(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine] was about tenfold more active than CDV, an observation that con rms earlier data of De Clercq et al.15 Of special interest is the fact that S-HPMPA has been reported to have activity against monkeypox and variola viruses at concentrations similar to those reported here for VV and CV.20 In the PMEA [9-(2-phosphonylmethoxyethyl) adenine] (adefovir) series, PMEA itself was not active. Similarly, the 2-phosphonylmethoxyethyl diaminopurine analogue of PMEA (PMEDAP), and the (R)-9-(2-phosphonylmethoxypropyl)adenine analogue (PMPA) (tenofovir) was inactive against VV and CV. In contrast, the 2-phosphonylmethoxyethyl guanine (PMEG) analogue was very active. From our ndings it appears that the compounds that merit additional studies include S-HPMPA, adefovir dipivoxil, and PMEG, as well as additional prodrugs of these nucleoside phosphonates. The major drawback to the development of one of these prodrugs is that little is known about their potential toxicology or their absorption, distribution, metabolism, or excretion in animals or humans and they would require all the same steps necessary for development of a new drug. The effectiveness of this group of compounds as antiviral agents and the continuing need to discover and develop compounds that may prove useful against orthopoxvirus infections have led to our evaluation of a variety of the prodrugs of CDV, S-HPMPA, PMEA, PMEDAP, or PMPA and/or related substituted analogues against two orthopoxviruses, VV and CV.39 The results of these studies can provide new information regarding new active compounds that may also be active orally and could be candidates for development as new therapeutic agents for poxvirus infections. In this series of studies, we rst determined the activity of a variety of CDV (HPMPC) analogues (Table 14.6). CDV, cyclic CDV (cHPMPC), and 2(butyl-oxycarbonyl) phenyl cHPMPC had similar 50% effective concentration (EC50) and SI values for both VV and CV in HFF cells. As indicated from previous studies,15,43 S-HPMPA was active against VV and, as determined in our studies, was also effective against CV and was the most active compound in this series. Both (phenethyl L-alaninyl) cHPMPC (mixture of diastereomers) and (butyl L-alaninyl) cHPMPC were ve- to sevenfold more active than HPMPC. In the PMEA series, PMEA itself was not active against VV or CV, but an orally active prodrug, bis[(pivaloyl)oxymethyl] PMEA (adefovir dipivoxil), was very active as was bis(butyl L-alaninyl) PMEA, with EC50 values of 4.4 13 mM. Similarly, the 2,6diaminopurine analogue of PMEA (PMEDAP) was inactive, whereas all the prodrugs were ef cacious against VV, but less active against CV. Antiviral activity was greatest for bis(butyl L-alaninyl) PME-N6-(cyclopropyl)DAP and (isopropyl L-alaninyl) phenyl PME-N6-(cyclopropyl)DAP. Not unexpectedly, the compounds with the best antiviral activities were generally the most toxic. PMPA and its oral prodrug tenofovir disoproxil fumarate {bis[(isopropoxycarbonyl)oxymethyl]PMPA} were both inactive against VV and CV replication, and the prodrug (isopropyl L-alaninyl) phenyl PMPA was only marginally active.
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