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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TABLE 14.6 Ef cacy and Cytotoxicity of HPMPC, S-HPMPA, PMEA, PMEDAP, PMPA, and Selected Prodrugs Against Vaccinia and Cowpox Viruses in HFF Cells Cytotoxicity Vaccinia Virus Compound HPMPC (CDV) cHPMPC 2-(Butyloxycarbonyl)phenylcHPMPC (Butyl L-alaninyl)cHPMPC (Phenethyl L-alaninyl)cHPMPC (mixed iastereomers) (S)-HPMPA PMEA Bis[(pivaloyl)oxymethyl]PMEA Bis (butyl L-alaninyl)PMEA PMEDAP PME-N6-(cyclopropyl) DAP Bis(butyl L-alaninyl) PME-N6-(cyclopropyl) DAP (Isopropyl L-alaninyl) phenyl-PME-N6-(cyclopropyl)DAP PME-N6-(tri uoroethyl)DAP PME-N6-(dimethyl)DAP PME-N6-(2-propenyl)DAP PMPA Bis[(isopropoxycarbonyl) oxymethyl]PMPA (Isopropyl L-alaninyl)phenyl PMPA
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Cowpox Virus EC50(mM) SI
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CC50 (mM) 278 9.2 >302 0 >213 22 >153 57 207 18
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EC50(mM) 33 9.1 38 11 32 13 4.6 0.8 7.1 0.3
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SI 8.4 >7.9 >6.7 >33 29
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43 2.5 6.5 48 8.0 >6.3 34 4.2 >6.3 8.4 5.3 >18 6.8 1.8 30 5.0 4.7 54 >366 0 13 8.8 9.0 10 8.2 10 >347 0 28 13 >9.4 0.26 0.2 189 2.6 1.9 >80 >6.0 >2.7 >1.4
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269 21 3.5 2.8 77 >366 0 >366 0 117 27 5.1 0.7 23 100 27 4.4 0.2 23 >339 12 204 15 1.7 >263 59 23 6.9 >11 49 33 0.08 0.01 613 >209 69 >270 0 >316 0 >305 0 >300 >157.4 >143 1.1 0.3 >190
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42 11 >6.4 >270 0 35 1.6 >9.0 53 8.3 25 0.9 >12 115 78 >300 >300 >157.4 >157.4 23.5 >6.1 98.9
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SI CC50/EC50 Source: Adapted from Keith, et al.39
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The results of these studies indicate that many of the acyclic nucleoside phosphonate analogues have potent and selective activity against orthopoxvirus infections. In particular, adefovir dipivoxil, which is active and orally bioavailable and is already approved for use in humans, should be considered a high priority for further evaluation as a treatment for smallpox and complications of VV vaccinations.
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14.5 DEVELOPMENT OF ALKOXYALKYL ESTER PRODRUGS OF CDV Previous studies have shown that alkyglycerol phosphate or alkoxypropyl phosphate esters of acyclovir44 and ganciclovir45 have greater oral bioavailability in rodents than the parent compounds. Furthermore, these compounds are active orally in animal models of herpesvirus disease45 and woodchuck hepatitis.46 To obtain
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DEVELOPMENT OF ALKOXYALKYL ESTER PRODRUGS OF CDV
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TABLE 14.7 Activitya of CDV and Alkoxyalkyl Analogues Against Cowpox Virus and Strains of Vaccinia Virus Compound CDV HDP-CDV ODE-CDV
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CV-BR 45 6.3 0.6 0.3 0.3 0.3
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VV-COP 46 12 0.8 0.4 0.2 0.1
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VV-WR 46 17 1.1 1.0 0.2 0.2
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VV-Elstree 42 22 1.2 0.8 0.4 0.1
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VV-IHD 13 6 0.2 0.0 0.1 0.0
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Values are the mean of two assays. Source: Adapted from Kern et al.21
better oral activity with CDV, a new series of analogues was synthesized using two long-chain alkoxyalkanols, hexadecyloxypropyl (HDP-CDV), and octadecyloxyethyl (ODE-CDV), and their activity compared with that of CDV in HFF cells infected with strains of VV or CV.21 The activity of CDV and the alkoxyalkyl analogues are presented in Table 14.7. Where CDV required about 10 50 mM to inhibit the replication of either CV or VV by 50%, the alkoxyalkyl analogue, HDPCDV, was active at about 0.6 and ODE-CDV at 0.3 against CV, respectively. The analogues were 75- to 150-fold more active than CDV against CV. All three of the nucleotides were similarly active against ve strains of VV; however, the IHD and NYC strains appeared to be more susceptible than the Copenhagen, WR, or Elstree strain. The EC50 values for HDP-CDV ranged from 0.20 1.2 mM, while ODE-CDV EC50 values were 0.10 0.40 mM, representing 28- to 209-fold increases in activity versus CDV for these same strains. In cytotoxicity assays, the HDP analogue was about ninefold more toxic than CDV and the ODE analogue nineteen-fold more toxic than CDV. The Selective Index (SI) value for CDV was about 6, whereas that for HDP-CDV was about 30, and for ODE-CDV 40 65, indicating that the analogues, although more toxic than the parent compounds, were more ef cacious, which resulted in higher SI values. A similar level of enhanced activity of HDPCDV and ODE-CDV has been reported for variola and monkeypox viruses 30,47 and ectromelia virus.48 The in vitro studies summarized above have shown multiple-log increases in antiviral activity against orthopoxvirus replication.21 Enhanced inhibition of cytomegalovirus, herpes simplex virus, and adenovirus replication by HDPCDV and ODE-CDV has also been reported.49,50 In order to evaluate the importance of chain length or linker type, additional analogues were synthesized by esteri cation of these compounds with an alkyl chain with or without the propoxy- or ethoxy-linker moieties.51 As presented in Table 14.8, the most active ether lipid esters of CDV were OLE-CDV, ODBG-CDV, TDP-CDV, OLP-CDV, and ODP-CDV, with 50% effective concentration (EC50) values of 0.06 1.2 mM for VV and 0.07 1.9 mM for CV (a 20- to 600-fold increase compared to the results seen with the parent compound). The majority of the new analogues tested were more active than the parent compounds, and structure activity analysis revealed that alkoxyalkyl or alkyl esters of CDV having chains shorter than 16 atoms beyond the phosphonate moiety of CDV were less active or inactive. Generally, optimal chain lengths were 20 atoms beyond the phosphonate,
342 Abbreviation CDV DDP-CDV TDP-CDV HDP-CDV ODP-CDV OLP-CDV ECP-CDV ODE-CDV OLE-CDV ODBG-CDV EC-CDV DC-CDV 45 8.5 73 8.8 47 24 21 8.8 56 29 0.2 0.1 0.06 0.02 0.4 0.1 1.6 1.3 10 1.7 105 933 118 28 7.3 >190 0 >100 0 29 2.3 44 14 87 15 92 1.4 6.6 0.9 0.5 0.2 0.6 0.4 1.2 0.5 0.4 0.2 2.0 0.9 >29 >200 48 37 218 46 >317 0 31 5.4 >10 Cytotoxicity CC50 (mM) Vaccinia Virus EC50 (mM) SIb 42 5.4 16 1.6 0.8 0.5 0.5 0.3 1.9 0.6 0.6 0.3 2.4 0.7 0.2 0.2 0.07 0.02 0.3 0.01 1.5 0.9 13 0.1 Cowpox Virus EC50 (mM) SI >7.5 >12 >125 58 23 145 38 105 800 157 30 5.6