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Expert Opinion on Drug Delivery Volume 6, 2009 - Issue 4
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Reviews

Prodrug approaches to improving the oral absorption of antiviral nucleotide analogues

Larryn W Peterson PhD candidate
&
Charles E McKenna Professor of Chemistry University of Southern California, Department of Chemistry, Los Angeles, CA 90089-0744, USA +1 213 740 7007; +1 213 740 0930; [email protected]
Pages 405-420 | Published online: 22 Apr 2009

Bibliography

  • De Clercq E. Antiviral drugs in current clinical use. J Clin Virol 2004;30(2):115-33
  • Rideout JL, Henry DW, Beacham LM III, Editors. Nucleosides, nucleotides, and their biological applications. (Proceedings of the 5th International Round Table, October 20-22, 1982). Academic Press: New York, 1983
  • Ariza ME. Current prodrug strategies for the delivery of nucleotides into cells. Drug Des Rev Online 2005;2(5):373-87
  • Hostetler KY. Synthesis and antiviral evaluation of broad spectrum, orally active analogs of cidofovir and other acyclic nucleoside phosphonates. Adv Antivir Drug Des 2007;5:167-84
  • Li F, Maag H, Alfredson T. Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting. J Pharm Sci 2008;97(3):1109-34
  • Wagner CR, Iyer VV, McIntee EJ. Pronucleotides: toward the in vivo delivery of antiviral and anticancer nucleotides. Med Res Rev 2000;20(6):417-51
  • Hillaireau H, Le Doan T, Appel M, Couvreur P. Hybrid polymer nanocapsules enhance in vitro delivery of azidothymidine-triphosphate to macrophages. J Control Release 2006;116(3):346-52
  • Vinogradov SV, Zeman AD, Batrakova EV, Kabanov AV. Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs. J Control Release 2005;107(1):143-57
  • Duzgunes N, Simoes S, Slepushkin V, et al. Delivery of antiviral agents in liposomes. Methods Enzymol 2005;391:351-73
  • Rossi L, Serafini S, Pierige F, et al. Erythrocyte-based drug delivery. Expert Opin Drug Deliv 2005;2(2):311-22
  • Aguzzi C, Cerezo P, Viseras C, Caramella C. Use of clays as drug delivery systems: possibilities and limitations. Appl Clay Sci 2007;36(1-3):22-36
  • McKenna CE, Kashemirov BA, Eriksson U, et al. Cidofovir peptide conjugates as prodrugs. J Organomet Chem 2005;690(10):2673-8
  • Anastasi C, Quelever G, Burlet S, et al. New antiviral nucleoside prodrugs await application. Curr Med Chem 2003;10(18):1825-43
  • Van de Waterbeemd H, Lennernas H, Artursson P. Drug bioavailability: estimation of solubility, permeability, absorption and bioavailability [In: Methods Princ. Med. Chem., 2003; 18], 2003
  • De Clercq E, Field HJ. Antiviral prodrugs – the development of successful prodrug strategies for antiviral chemotherapy. Br J Pharmacol 2006;147(1):1-11
  • Schultz C. Prodrugs of biologically active phosphate esters. Biorg Med Chem 2003;11(6):885-98
  • Painter GR, Hostetler KY. Design and development of oral drugs for the prophylaxis and treatment of smallpox infection. Trends Biotechnol 2004;22(8):423-7
  • Quenelle DC, Collins DJ, Wan WB, et al. Oral treatment of cowpox virus and vaccinia virus infections in mice with ether lipid esters of cidofovir. Antimicrob Agents Chemother 2004;48(2):404-12
  • Perrone P, Luoni GM, Kelleher MR, et al. Application of the phosphoramidate ProTide approach to 4'-azidouridine confers sub-micromolar potency versus Hepatitis C virus on an inactive nucleoside. J Med Chem 2007;50(8):1840-9
  • Perrone P, Daverio F, Valente R, et al. First example of phosphoramidate approach applied to a 4′-substituted purine nucleoside (4′-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus Hepatitis C virus. J Med Chem 2007;50(22):5463-70
  • Mehellou Y, McGuigan C, Brancale A, Balzarini J. Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate ‘ProTide’ derivatives. Bioorg Med Chem Lett 2007;17(13):3666-9
  • McGuigan C, Hassan-Abdallah A, Srinivasan S, et al. Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives. J Med Chem 2006;49(24):7215-26
  • Balzarini J, Karlsson A, Aquaro S, et al. Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives. Proc Natl Acad Sci USA 1996;93(14):7295-9
  • Ballatore C, McGuigan C, De Clercq E, Balzarini J. Synthesis and evaluation of novel amidate prodrugs of PMEA and PMPA. Bioorg Med Chem Lett 2001;11(8):1053-6
  • McGuigan C, Pathirana RN, Mahmood N, et al. Aryl phosphates derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT. Antiviral Res 1992;17(4):311-21
  • Balzarini J, Aquaro S, Hassan-Abdallah A, et al. Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5'-triphosphate metabolite levels. FEBS Lett 2004;573(1-3):38-44
  • Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother 2005;49(5):1898-906
  • Cahard D, McGuigan C, Balzarini J. Aryloxy phosphoramidate triesters as protides. Mini Rev Med Chem 2004;4(4):371-81
  • McGuigan C, Nickson C, O'Connor TJ, Kinchington D. Synthesis and anti-HIV activity of some novel lactyl and glycolyl phosphate derivatives. Antiviral Res 1992;17(3):197-212
  • McGuigan C, Pathirana RN, Davies MPH, et al. Diaryl phosphate derivatives act as pro-drugs of AZT with reduced cytotoxicity compared to the parent nucleoside. Bioorg Med Chem Lett 1994;4(3):427-30
  • Venkatachalam TK, Samuel P, Qazi S, Uckun FM. Effect of change in nucleoside structure on the activation and antiviral activity of phosphoramidate derivatives. Biorg Med Chem 2005;13(18):5408-23
  • McGuigan C, Sutton PW, Cahard D, et al. Synthesis, anti-human immunodeficiency virus activity and esterase lability of some novel carboxylic ester-modified phosphoramidate derivatives of stavudine (d4T). Antivir Chem Chemother 1998;9(6):473-9
  • Knaggs MH, McGuigan C, Harris SA, et al. A QSAR study investigating the effect of l-alanine ester variation on the anti-HIV activity of some phosphoramidate derivatives of d4T. Bioorg Med Chem Lett 2000;10(18):2075-8
  • Saboulard D, Naesens L, Cahard D, et al. Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. Mol Pharmacol 1999;56(4):693-704
  • McGuigan C, Harris SA, Daluge SM, et al. Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency. J Med Chem 2005;48(10):3504-15
  • McGuigan C, Tsang HW, Cahard D, et al. Phosphoramidate derivatives of d4T as inhibitors of HIV: the effect of amino acid variation. Antiviral Res 1997;35(3):195-204
  • Siddiqui AQ, Ballatore C, McGuigan C, et al. The presence of substituents on the aryl moiety of the aryl phosphoramidate derivative of d4T enhances anti-HIV efficacy in cell culture: a structure–activity relationship. J Med Chem 1999;42(3):393-9
  • Congiatu C, McGuigan C, Jiang WG, et al. Naphthyl phosphoramidate derivatives of BVdU as potential anticancer agents: design, synthesis and biological evaluation. Nucleosides Nucleotides Nucleic Acids 2005;24(5-7):485-9
  • Siccardi D, Gumbleton M, Omidi Y, McGuigan C. Stereospecific chemical and enzymatic stability of phosphoramidate triester prodrugs of d4T in vitro. Eur J Pharm Sci 2004;22(1):25-31
  • Mucha A, Grembecka J, Cierpicki T, Kafarski P. Hydrolysis of the phosphonamidate bond in phosphono dipeptide analogs – the influence of the nature of the N-terminal functional group. Eur J Org Chem 2003;2003(24):4797-803
  • Siccardi D, Kandalaft LE, Gumbleton M, McGuigan C. Stereoselective and concentration-dependent polarized epithelial permeability of a series of phosphoramidate triester prodrugs of d4T: An in vitro study in Caco-2 and Madin-Darby canine kidney cell monolayers. J Pharmacol Exp Ther 2003;307(3):1112-9
  • Chang SL, Griesgraber GW, Southern PJ, Wagner CR. Amino acid phosphoramidate monoesters of 3′-azido-3′-deoxythymidine: relationship between antiviral potency and intracellular metabolism. J Med Chem 2001;44(2):223-31
  • McIntee EJ, Remmel RP, Schinazi RF, et al. Probing the mechanism of action and decomposition of amino acid phosphomonoester amidates of antiviral nucleoside prodrugs. J Med Chem 1997;40(21):3323-31
  • Chang SL, Griesgraber G, Wagner CR. Comparison of the antiviral activity of hydrophobic amino acid phosphoramidate monoesters of 2′,3′-dideoxyadenosine (DDA) and 3'-azido-3′-deoxythymidine (AZT). Nucleosides, Nucleotides Nucleic Acids 2001;20(8):1571-82
  • Abraham TW, Kalman TI, McIntee EJ, Wagner CR. Synthesis and biological activity of aromatic amino acid phosphoramidates of 5-fluoro-2′-deoxyuridine and 1-beta -arabinofuranosylcytosine: Evidence of phosphoramidase activity. J Med Chem 1996;39(23):4569-75
  • Molema G, Jansen RW, Pauwels R, et al. Targeting of antiviral drugs to T4-lymphocytes. Anti-HIV activity of neoglycoprotein-AZTMP conjugates in vitro. Biochem Pharmacol 1990;40(12):2603-10
  • Wagner CR, McIntee EJ, Schinazi RF, Abraham TW. Aromatic amino acid phosphoramidate di- and triesters of 3′-azido-3′-deoxythymidine (AZT) are non-toxic inhibitors of HIV-1 replication. Bioorg Med Chem Lett 1995;5(16):1819-24
  • Song H, Griesgraber George W, Wagner Carston R, Zimmerman Cheryl L. Pharmacokinetics of amino acid phosphoramidate monoesters of zidovudine in rats. Antimicrob Agents Chemother 2002;46(5):1357-63
  • Drontle DP, Wagner CR. Designing a pronucleotides stratagem: lessons from amino acid phosphoramidates of anticancer and antiviral pyrimidines. Mini Rev Med Chem 2004;4(4):409-19
  • Song H, Johns R, Griesgraber GW, et al. Disposition and oral bioavailability in rats of an antiviral and antitumor amino acid phosphoramidate prodrug of AZT-monophosphate. Pharm Res 2003;20(3):448-51
  • Huskey SEW, Luffer-Atlas D, Dean BJ, et al. Substance P receptor antagonist. I: Conversion of phosphoramidate prodrug after i.v. administration to rats and dogs. Drug Metab Dispos 1999;27(11):1367-73
  • Girardet JL, Perigaud C, Aubertin AM, et al. Increase of the anti-HIV activity of D4T in human T-cell culture by the use of the sate pronucleotide approach. Bioorg Med Chem Lett 1995;5(24):2981-4
  • Annaert P, Gosselin G, Pompon A, et al. Comparison of the disposition of ester prodrugs of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA] in Caco-2 monolayers. Pharm Res 1998;15(2):239-45
  • Li X, Carmichael E, Feng M, et al. Bis-S-acyl-2-thioethyl (SATE)-bearing 5′-monophosphate prodrug of beta-L-FD4C as potent anti-HBV agent. Bioorg Med Chem Lett 1998;8(1):57-62
  • Perigaud C, Gosselin G, Girardet JL, et al. The S-acyl-2-thioethyl pronucleotide approach applied to acyclovir. Part I. Synthesis and in vitro anti-hepatitis B virus activity of bis(S-acyl-2-thioethyl)phosphotriester derivatives of acyclovir. Antiviral Res 1999;40(3):167-78
  • Hantz O, Perigaud C, Borel C, et al. The SATE pronucleotide approach applied to acyclovir. Part II. Effects of bis(SATE)phosphotriester derivatives of acyclovir on duck hepatitis B virus replication in vitro and in vivo. Antiviral Res 1999;40(3):179-87
  • Villard AL, Coussot G, Lefebvre I, et al. Phenyl phosphotriester derivatives of AZT: variations upon the SATE moiety. Bioorg Med Chem 2008;16(15):7321-9
  • Egron D, Imbach JL, Gosselin G, et al. S-Acyl-2-thioethyl phosphoramidate diester derivatives as mono-nucleotide prodrugs. J Med Chem 2003;46(21):4564-71
  • Peyrottes S, Villard AL, Coussot G, et al. A step further in the SATE mononucleotide prodrug approach. Nucleic Acids Symp Ser 2008;52(1):539-40
  • Groschel B, Cinatl J, Perigaud C, et al. S-acyl-2-thioethyl (SATE) pronucleotides are potent inhibitors of HIV-1 replication in T-lymphoid cells cross-resistant to deoxycytidine and thymidine analogs. Antiviral Res 2002;53(2):143-52
  • Peyrottes S, Egron D, Lefebvre I, et al. SATE pronucleotide approaches: an overview. Mini Rev Med Chem 2004;4(4):395-408
  • Shafiee M, Deferme S, Villard AL, et al. New bis(SATE) prodrug of AZT 5′-monophosphate: in vitro anti-HIV activity, stability, and potential oral absorption. J Pharm Sci 2001;90(4):448-63
  • Schlienger N, Beltran T, Perigaud C, et al. Rational design of a new series of mixed anti-HIV pronucleotides. Bioorg Med Chem Lett 1998;8(21):3003-6
  • Coussot G, Lefebvre I, Dimalta D, et al. SATE (aryl) phosphotriester series. II. Stability studies and physicochemical parameters. Nucleosides Nucleotides Nucleic Acids 2003;22(5-8):907-9
  • Jochum A, Schlienger N, Egron D, et al. Biolabile constructs for pronucleotide design. J Organomet Chem 2005;690(10):2614-25
  • Peyrottes S, Gosselin G, Aubertin AM, Perigaud C. SATE (aryl) phosphotriester series. I. Synthesis and biological evaluation. Nucleosides Nucleotides Nucleic Acids 2003;22(5-8):903-5
  • Beltran T, Egron D, Pompon A, et al. Rational design of a new series of pronucleotide. Bioorg Med Chem Lett 2001;11(13):1775-7
  • Meier C. cycloSal-pronucleotides – design of chemical Trojan horses. Mini Rev Med Chem 2002;2(3):219-34
  • Meerbach A, Klocking R, Meier C, et al. Inhibitory effect of cycloSaligenyl-nucleoside monophosphates (cycloSal-NMP) of acyclic nucleoside analogues on HSV-1 and EBV. Antiviral Res 2000;45(1):69-77
  • Goerbig U, Balzarini J, Meier C. New cycloAMB-nucleoside phosphonate prodrugs. Nucleosides Nucleotides Nucleic Acids 2007;26(6-7):831-4
  • Meier C, Knispel T, De Clercq E, Balzarini J. CycloSal-pronucleotides of 2′,3′-dideoxyadenosine and 2′,3′-dideoxy-2′, 3'-didehydroadenosine: Synthesis and antiviral evaluation of a highly efficient nucleotide delivery system. J Med Chem 1999;42(9):1604-14
  • Meier C, Meerbach A, Wutzler P. CycloSal-pronucleotides of brivudine monophosphate – highly active antiviral agents. Curr Med Chem Anti-Infect Agents 2005;4(4):317-35
  • Jessen HJ, Tonn V, Meier C. Intracellular trapping of cycloSal-pronucleotides by enzymatic cleavage. Nucleosides Nucleotides Nucleic Acids 2007;26(6-7):827-30
  • Gisch N, Balzarini J, Meier C. 5-diacetoxymethyl-cycloSal-d4TMP – A prototype of enzymatically activated cycloSal-pronucleotides. Nucleosides Nucleotides Nucleic Acids 2007;26(6-7):861-4
  • Gisch N, Balzarini J, Meier C. Enzymatically activated cycloSal-d4T-monophosphates: the third generation of cycloSal-pronucleotides. J Med Chem 2007;50(7):1658-67
  • Meier C, Ducho C, Jessen H, et al. Second-generation cycloSal-d4TMP pro-nucleotides bearing esterase-cleavable sites – the ‘trapping’ concept. Eur J Org Chem 2006;2006(1):197-206
  • Gisch N, Pertenbreiter F, Balzarini J, Meier C. 5-(1-Acetoxyvinyl)-cycloSaligenyl-2',3'-dideoxy-2',3'- didehydrothymidine monophosphates, a second type of new, enzymatically activated cycloSaligenyl pronucleotides. J Med Chem 2008;51(24):8115-23
  • Vukadinovic-Tenter D, Balzarini J, Meier C. New developments of the ‘lock-in’ modified cycloSal-d4TMPs. Nucleosides Nucleotides Nucleic Acids 2007;26(10-12):1325-8
  • Gisch N, Balzarini J, Meier C. Studies on enzyme-cleavable dialkoxymethyl-cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine monophosphates. J Med Chem 2008;51(21):6752-60
  • Ludek OR, Balzarini J, Meier C. Synthesis and antiviral evaluation of carbocyclic 3'-azidothymidine (AZT) analogs and their cycloSal-phosphate triesters. Eur J Org Chem 2006;2006(4):932-40
  • Meier C, Balzarini J. Application of the cycloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules. Antiviral Res 2006;71(2-3):282-92
  • Meier C. CycloSal phosphates as chemical Trojan horses for intracellular nucleotide and glycosyl-monophosphate delivery – chemistry meets biology. Eur J Org Chem 2006;2006(5):1081-102
  • Meier C, Lorey M, De Clercq E, Balzarini J. cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system. J Med Chem 1998;41(9):1417-27
  • Jessen HJ, Balzarini J, Meier C. Intracellular trapping of cycloSal-pronucleotides: Modification of prodrugs with amino acid esters. J Med Chem 2008;51(20):6592-8
  • Meier C, Ruppel MFH, Vukadinovic D, Balzarini J. ‘Lock-in’-cycloSal-pronucleotides – a new generation of chemical Trojan horses? Mini Rev Med Chem 2004;4(4):383-94
  • Ducho C, Balzarini J, Meier C. Non-inhibition of acetylcholinesterase by cycloSal nucleotides. Nucleosides Nucleotides Nucleic Acids 2003;22(5-8):841-3
  • Meier C, Ducho C, Goerbig U, et al. Interaction of cycloSal-pronucleotides with cholinesterases from different origins. A structure–activity relationship. J Med Chem 2004;47(11):2839-52
  • Ducho C, Jessel S, Gisch N, et al. Novel cycloSal nucleotides with reduced inhibitory potency toward human butyrylcholinesterase. Nucleosides Nucleotides Nucleic Acids 2005;24(5-7):519-22
  • Ducho C, Goerbig U, Jessel S, et al. Bis-cycloSal-d4T-monophosphates: Drugs that deliver two molecules of bioactive nucleotides. J Med Chem 2007;50(6):1335-46
  • Eriksson U, Hilfinger JM, Kim JS, et al. Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir. Bioorg Med Chem Lett 2007;17(3):583-6
  • Peterson LW, Kashemirov BA, Saejueng K, et al. Novel synthetic approaches to cidofovir and foscarnet prodrugs. Antiviral Res 2007;74(3):A74
  • Eriksson U, Peterson LW, Kashemirov BA, et al. Serine peptide phosphoester prodrugs of cyclic cidofovir: Synthesis, transport, and antiviral activity. Mol Pharm 2008;5(4):598-609
  • Peterson LW, Kashemirov BA, Sala-Rabanal M, et al. Synthesis and transport studies on serine side-chain-linked peptidomimetic prodrugs of cyclic cidofovir. Abstracts of Papers, 235th ACS National Meeting, New Orleans, LA, USA, April 6-10, 2008 2008:MEDI-183
  • Soul-Lawton J, Seaber E, On N, et al. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob Agents Chemother 1995;39(12):2759-64
  • Han HK, Amidon GL. Targeted prodrug design to optimize drug delivery. AAPS PharmSci 2000;2(1):E6
  • Savle PS, Shelton TE, Meadows CA, et al. N-(Cyclohexanecarboxyl)-O-phospho-L-serine, a minimal substrate for the dual-specificity protein phosphatase IphP. Arch Biochem Biophys 2000;376(2):439-48
  • Pestell KE, Ducruet AP, Wipf P, Lazo JS. Small molecule inhibitors of dual specificity protein phosphatases. Oncogene 2000;19(56):6607-12
  • Peterson LW, Kashemirov BA, Blazewska KM, et al. Synthesis and structure-activity aspects of some cyclic cidofovir peptidomimetic prodrugs. Antiviral Res 2007;74(3):A33
  • Mendel DB, Cihlar T, Moon K, Chen MS. Conversion of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine to cidofovir by an intracellular cyclic CMP phosphodiesterase. Antimicrob Agents Chemother 1997;41(3):641-6
  • Williams RE, Lock EA. Sodium benzoate attenuates D-serine induced nephrotoxicity in the rat. Toxicology 2005;207(1):35-48
  • Parrott N, Jones H, Paquereau N, Lave T. Application of full physiological models for pharmaceutical drug candidate selection and extrapolation of pharmacokinetics to man. Basic Clin Pharmacol Toxicol 2005;96(3):193-9

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