Prodrugs pp 801-831 | Cite as

Prodrugs of Amines

  • Jeffrey P. Krise
  • Reza Oliyai
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume V)


The amine group is one of the most frequently found functional groups in today’s armory of commercially available drugs. Like many pharmaceuticals, compounds containing an amine can have physicochemical attributes that present obstacles to their safe and effective delivery to desired sites of action. Amines are generally considered to be amenable to derivatization reactions and thus provide a “synthetic handle” that can be exploited in chemical modifications. As a result, numerous prodrugs of amines have been evaluated in an effort to overcome formulation and delivery barriers, which include low aqueous solubility, toxicity of the vehicle, poor membrane permeability, chemical and metabolic instability, and lack of specificity


Tertiary Amine Carbamic Acid Soft Drug Prodrug Approach Parent Amine 
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  1. Albert DH, Conway RG, Magoc TJ, Tapang P, Rhein DA, Luo G, Holms JH, Davidsen SK, Summers JB, and Carter GW. Properties of ABT-299, A Prodrug of A-85783, a Highly Potent Platelet Activating Factor Receptor Antagonist. J Pharmacol Exp Ther 1996; 277:1595–1606PubMedGoogle Scholar
  2. Albert DH, Magoc TJ, Menacherry SD, Morgan DW, Sun E, Reyes AE, Kleinert HD, Carter GW, and Summers JB. Ex Vivo Inhibition of beta-Thromboglobulin Release Following Administration to Man of ABT-299, a Novel Prodrug of a Potent Platelet Activating Factor Antagonist. Inflamm Res 1997; 46:272–277PubMedGoogle Scholar
  3. Alexander J, Cargill R, Michelson SR, and Schwam H. (Acyloxy)alkyl Carbamates as Novel Bioreversible Prodrugs for Amines: Increased Permeation through Biological Membranes. J Med Chem 1988; 31:318–322PubMedGoogle Scholar
  4. Amsberry KL, and Borchardt RT. The Lactonization of 2′-Hydroxyhydrocinnamic Acid Amides: A Potential Prodrug for Amines. J Org Chem 1990; 55:5867–5877Google Scholar
  5. Amsberry KL, and Borchardt RT. Amine Prodrugs which Utilize Hydroxy Amide Lactonization. I. A Potential Redox-sensitive Amide Prodrug. Pharm Res 1991; 8:323–330PubMedGoogle Scholar
  6. Amsberry KL, Gerstenberger AE, and Borchardt RT. Amine Prodrugs which Utilize Hydroxy Amide Lactonization. II. A Potential Esterase-sensitive Amide Prodrug. Pharm Res 1991; 8:455–461PubMedGoogle Scholar
  7. Anastasi C, Quelever G, Burlet S, Garino C, Souard F, and Kraus JL. New Antiviral Nucleoside Prodrugs Await Application. Curr Med Chem 2003; 10:1825–1843PubMedGoogle Scholar
  8. Anastasi C, Hantz O, De Clercq E, Pannecouque C, Clayette P, Dereuddre-Bosquet N, Dormont D, Gondois-Rey F, Hirsch I, and Kraus JL. Potent Nonclassical Nucleoside Antiviral Drugs Based on the N,N-diarylformamidine Concept. J Med Chem 2004; 47:1183–1192PubMedGoogle Scholar
  9. Belke CJ, Su SC, and Shafer JA. Imidazole-catalyzed Displacement of an Amine from an Amide by a Neighboring Hydroxyl Group. A Model for the Acylation of Chymotrypsin. J Am Chem Soc 1971; 93:4552–4560PubMedGoogle Scholar
  10. Bodor N. Soft Drugs: Principles and Methods for the Design of Safe Drugs. Med Res Rev 1984; 4:449–469PubMedGoogle Scholar
  11. Bodor N, and Kaminski JJ. Soft Drugs. 2. Soft Alkylating Compounds as Potential Antitumor Agents. J Med Chem 1980; 23:566–569PubMedGoogle Scholar
  12. Bodor N, and Farag HH. Improved Delivery through Biological Membranes. 11. A Redox Chemical Drug-Delivery System and its Use for Brain-specific Delivery of Phenylethylamine. J Med Chem 1983a; 26:313–318PubMedGoogle Scholar
  13. Bodor N, and Farag HH. Improved Delivery through Biological Membranes. 13. Brain-specific Delivery of Dopamine with a Dihydropyridine in Equilibrium with Pyridinium Salt Type Redox Delivery System. J Med Chem 1983b; 26:528–534PubMedGoogle Scholar
  14. Bodor N, Kaminski JJ, and Selk S. Soft drugs. 1. Labile Quaternary Ammonium Salts as Soft Antimicrobials. J Med Chem 1980a; 23:469–474PubMedGoogle Scholar
  15. Bodor N, Woods R, Raper C, Kearney P, and Kaminski JJ. Soft Drugs. 3. A New Class of Anticholinergic Agents. J Med Chem 1980b; 23:474–480PubMedGoogle Scholar
  16. Bogardus JB, and Higuchi T. Kinetics and Mechanism of Hydrolysis of Labile Quaternary Ammonium Derivatives of Tertiary Amines. J Pharm Sci 1982; 71:729–735PubMedGoogle Scholar
  17. Brown JM. The hypoxic cell: A Target for Selective Cancer Therapy—Eighteenth Bruce F. Cain Memorial Award Lecture. Cancer Res 1999; 59:5863–5870PubMedGoogle Scholar
  18. Bundgaard H. Design of Prodrugs: Bioreversible Derivatives for Various Functional Groups and Chemical Entities. In: Bundgaard H. Design of Prodrugs. Amsterdam, Elsevier Science Publishers; 1985:1–92Google Scholar
  19. Bundgaard H., and Johansen M. Pro-drugs as Drug Delivery Systems XIX. Bioreversible Derivatization of Aromatic Amines by Formation of N-Mannich Bases with Succinimide. Int J Pharm 1981; 8:183–192Google Scholar
  20. Bundgaard H, and Johansen M. Pro-drugs as Drug Delivery Systems XX. Oxazolidines as Potential Pro-drug Types for beta-Aminoalcohols, Adehydes or Ketones, Int J Pharm 1982; 10:165–175Google Scholar
  21. Bundgaard H, and Falch, E. Allopurinol prodrugs. I. Synthesis, Stability and Physicochemical Properties of Various N1-acyl Allopurinol Derivatives. Int J Pharm 1985; 23:223–237Google Scholar
  22. Cain BF. 2-Acyloxymethylbenzoic Acids. Novel Amine Protective Functions Providing Amides with the Lability of Esters. J Org Chem 1976; 41:2029–2031Google Scholar
  23. Carl PL, Chakravarty PK, and Katzenellenbogen JA, Weber MJ. Protease-activated “Prodrugs” for Cancer Chemotherapy. Proc Natl Acad Sci USA 1980; 77:2224–2228PubMedGoogle Scholar
  24. Carl PL, Chakravarty PK, and Katzenellenbogen JA. A Novel Connector Linkage Applicable in Prodrug Design. J Med Chem 1981; 24:479–480PubMedGoogle Scholar
  25. Chakravarty PK, Carl PL, Weber MJ, and Katzenellenbogen JA. Plasmin-activated Prodrugs or Cancer Chemotherapy. 1. Synthesis and Biological Activity of Peptidylacivicin and Peptidylphenylenediamine Mustard. J Med Chem 1983a; 26:633–638PubMedGoogle Scholar
  26. Chakravarty PK, Carl PL, Weber MJ, and Katzenellenbogen JA. Plasmin-activated Prodrugs or Cancer Chemotherapy. 2. Synthesis and Biological Activity of Peptidyl Derivatives of Doxorubicin. J Med Chem 1983b; 26:638–644PubMedGoogle Scholar
  27. Chasseaud LF. Reaction with Electrophiles after Enzyme-catalysed Deacetylation of N-acetylcysteine. Biochem Pharmacol 1974; 23:1133–1134PubMedGoogle Scholar
  28. Chiong KN, Lewis SD, and Shaffer JA. Rationalization of the Rate of the Acylation Step in Chymotrypsin-catalyzed Hydrolysis of Amides. J Am Chem Soc 1975; 97:418–423PubMedGoogle Scholar
  29. Chourasia MK, and Jain SK. Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Pharm Sci 2003; 6:33–66PubMedGoogle Scholar
  30. Cogan PS, and Koch TH. Rational Design and Synthesis of Androgen Receptor-targeted Nonsteroidal Anti-androgen Ligands for the Tumor-specific delivery of a Doxorubicin-Formaldehyde Conjugate. J Med Chem 2003; 46:5258–5270PubMedGoogle Scholar
  31. Cogan PS, Fowler CR, Post GC, and Koch TH. Doxsaliform: A Novel N-Mannich Base Prodrug of a Doxorubicin Formaldehyde Conjugate. Lett Drug Des Disc 2004; 1:247–255Google Scholar
  32. Cooper JC. Review of the Environmental Toxicity of Quaternary Ammonium Halides. Ecotoxicol Environ Saf 1988; 16:65–71PubMedGoogle Scholar
  33. Cruz DN. Midodrine: A Selective alpha-Adrenergic Agonist for Orthostatic Hypotension and Dialysis Hypotension. Expert Opin Pharmacother 2000; 1:835–840PubMedGoogle Scholar
  34. Davidsen SK, Summers JB, Albert DH, Holms JH, Heyman HR, Magoc TJ, Conway RG, Rhein DA, and Carter GW. N-(acyloxyalkyl)pyridinium Salts as Soluble Prodrugs of a Potent Platelet Activating Factor Antagonist. J Med Chem 1994; 37:4423–4429PubMedGoogle Scholar
  35. de Groot FM, de Bart AC, Verheijen JH, and Scheeren HW. Synthesis and Biological Evaluation of Novel Prodrugs of Anthracyclines for Selective Activation by the Tumor-associated Protease Plasmin. J Med Chem 1999; 42:5277–5283PubMedGoogle Scholar
  36. de Groot FM, Loos WJ, Koekkoek R, van Berkom LW, Busscher GF, Seelen AE, Albrecht C, de Bruijn P, and Scheeren HW. Elongated Multiple Electronic Cascade and Cyclization Spacer Systems in Activatible Anticancer Prodrugs for Enhanced Drug Release. J Org Chem 2001; 66:8815–8830PubMedGoogle Scholar
  37. Denny WA. Tumor-activated Prodrugs—A New Approach to Cancer Therapy. Cancer Invest 2004; 22:604–619PubMedGoogle Scholar
  38. Dimmock JR, Arora VK, Chen M, Allen TM, and Kao GY. Cytotoxic Evaluation of Some N-acyl and N-acyloxy Analogues of 3,5-bis(Arylidene)-4-piperidones. Drug Des Discov 1994; 12:19–28PubMedGoogle Scholar
  39. Drieman JC, Thijssen HH, and Struyker-Boudier HA. Renal Selective N-Acetyl-L-gamma-glutamyl Prodrugs: Studies on the Selectivity of Some Model Prodrugs. Br J Pharmacol 1993; 108:204–208PubMedGoogle Scholar
  40. Evers JL, Patel J, Madeja JM, Schneider SL, Hobika GH, Camiolo SM, and Markus G. Plasminogen Activator Activity and Composition in Human Breast Cancer. Cancer Res 1982; 42:219–226PubMedGoogle Scholar
  41. Fenick DJ, Taatjes DJ, and Koch TH. Doxoform and Daunoform: Anthracyclineformaldehyde Conjugates Toxic to Resistant Tumor Cells. J Med Chem 1997; 40:2452–2461PubMedGoogle Scholar
  42. Fernandez C., Nieto O., Rivas E., Montenegro G., Fontenla JA, and Fernandez-Mayoralas A. Synthesis and Biological Studies of Glycosyl Dopamine Derivatives as Potential Antiparkinsonian Agents. Carbohydr Res 2000; 327:353–365PubMedGoogle Scholar
  43. Fife TH, and Benjamin, BM. Intramolecular General Base Catalysed Alcoholysis of Amides. J Chem Soc Chem Comm 1974; 14:525–526Google Scholar
  44. Fife TH, and DeMark BR. Intramolecular Nucleophilic Aminolysis of Aliphatic Esters. Cyclization of Methyl 2-Aminomethylbenzoate to Phthalimidine. J Am Chem Soc 1976; 98:6978–6982PubMedGoogle Scholar
  45. Gogate US, and Repta AJ. N-(Acyloxyalkoxycarbonyl) Derivatives as Potential Prodrugs of Amines. II. Esterase-catalyzed Release of Parent Amines from Model Prodrugs. Int J Pharm 1987; 40:249–255Google Scholar
  46. Gogate US, Repta AJ, and Alexander J. N-(Acyloxyalkoxycarbonyl) Derivatives as Potential Prodrugs of Amines. I. Kinetics and Mechanism of Degradation in Aqueous Solutions. Int J Pharm 1987; 40:235–248Google Scholar
  47. Greenwald RB, Pendri A, Conover CD, Zhao H, Choe YH, Martinez A, Shum K, and Guan S. Drug Delivery Systems Employing 1,4-or 1,6-Elimination: Poly(ethylene glycol) Prodrugs of Amine-containing Compounds. J Med Chem 1999; 42:3657–3667PubMedGoogle Scholar
  48. Higuchi T, Lee HK, and Pittman IH. Analysis of Possible Accelerating Influence of Irreversible Chemical Reactions on Dissolution Rates of Reactive Solids. Dissolution Behavior of 7-Acetyltheophylline. Farm Aikak 1971; 80:55–90Google Scholar
  49. Hu L. Prodrug Approaches to Drug Delivery. In: Wang B, Siahaan T, and Soltero RA. Drug Delivery: Principles and Applications. Hoboken, NJ, John Wiley and Sons, Inc.; 2005:125–166Google Scholar
  50. Ichikawa T, Kitazaki T, Matsushita Y, Yamada M, Hayashi R, Yamaguchi M, Kiyota Y, Okonogi K, and Itoh K. Optically Active Antifungal Azoles. XII. Synthesis and Antifungal Activity of the Water-soluble Prodrugs of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone. Chem Pharm Bull (Tokyo) 2001; 49:1102–1109Google Scholar
  51. Jensen NP, Friedman JJ, Kropp H, and Kahan FM. Use of Acetylacetone to Prepare a Prodrug of Cycloserine. J Med Chem 1980; 23:6–8PubMedGoogle Scholar
  52. Johansen M, and Bundgaard, H. Pro-drugs as Drug Delivery Systems XIII. Kinetics of Decomposition of N-Mannich Bases of Salicylamide and Assessment of their Suitability as Possible Pro-drugs for Amines. Int J Pharm 1980; 7:119–127Google Scholar
  53. Johansen M, and Bundgaard H. Prodrugs as drug delivery systems XXV: Hydrolysis of Oxazolidines—A Potential New Prodrug Type. J Pharm Sci 1983; 72:1294–1298PubMedGoogle Scholar
  54. Kopecek J, Kopeckova P, Brondsted H, Rathi R, Rihova B, Yeh PY, and Ikesue K. Polymers for Colon-specific Drug Delivery. J Control Rel 1992; 19:121–130Google Scholar
  55. Krause M, Rouleau A, Stark H, Garbarg M, Schwartz JC, and Schunack W. Structure-activity Relationships of Novel Azomethine Prodrugs of the Histamine H3-receptor agonist (R)-alpha-Methylhistamine: From Alkylaryl to Substituted Diaryl Derivatives. Pharmazie 1996; 51:720–726PubMedGoogle Scholar
  56. Krise JP, Zygmunt J, Georg GI, and Stella VJ. Novel Prodrug Approach for Tertiary Amines: Synthesis and Preliminary Evaluation of Nphosphonooxymethyl Prodrugs. J Med Chem 1999a; 42:3094–3100PubMedGoogle Scholar
  57. Krise JP, Narisawa S, and Stella VJ. A Novel Prodrug Approach for Tertiary amines. 2. Physicochemical and In Vitro Enzymatic Evaluation of selected Nphosphonooxymethyl Prodrugs. J Pharm Sci 1999b; 88:922–927PubMedGoogle Scholar
  58. Krise JP, Charman WN, Charman SA, and Stella VJ. A Novel Prodrug Approach for Tertiary Amines. 3. In Vivo Evaluation of Two N-phosphonooxymethyl Prodrugs in Rats and Dogs. J Pharm Sci 1999c; 88:928–32PubMedGoogle Scholar
  59. Kupchan SM, and Isenberg AC. Drug Latentiation. 3. Labile Amide Derivatives of Normeperidine. J Med Chem 1967; 10:960–961PubMedGoogle Scholar
  60. Larsen SW, Sidenius M, Ankersen M, and Larsen C. Kinetics of Degradation of 4-imidazolidinone Prodrug Types Obtained from Reacting Prilocaine with Formaldehyde and Acetaldehyde. Eur J Pharm Sci 2003; 20:233–240PubMedGoogle Scholar
  61. Lee HK, Lambert H, Stella VJ, Wang D, and Higuchi T. Hydrolysis and Dissolution Behavior of Prolonged-release Prodrug of Theophylline: 7,7′-Succinylditheophylline. J Pharm Sci 1979; 68:288–295PubMedGoogle Scholar
  62. Mauger AB, Burke PJ, Somani HH, Friedlos F, and Knox RJ. Self-immolative Prodrugs: Candidates for Antibody-directed Enzyme Prodrug Therapy in Conjunction with a Nitroreductase Enzyme. J Med Chem 1994; 37:3452–3458PubMedGoogle Scholar
  63. McClellan KJ, Wiseman LR, and Wilde MI. Midodrine. A Review of Its Therapeutic use in the Management of Orthostatic Hypotension. Drugs Aging 1998; 12:76–86PubMedGoogle Scholar
  64. Murakami T, Tamauchi H, Yamazaki M, Kubo K, Kamada A, and Yata N. Biopharmaceutical Study on the Oral and Rectal Administrations of Enamine Prodrugs of Amino Acid-like beta-Lactam Antibiotics in Rabbits. Chem Pharm Bull (Tokyo) 1981; 29:1986–1997Google Scholar
  65. Naringrekar VH, and Stella VJ. Mechanism of Hydrolysis and Structure-stability Relationship of Enaminones as Potential Prodrugs of Model Primary Amines. J Pharm Sci 1990; 79:138–146PubMedGoogle Scholar
  66. Nielsen NM, and Bundgaard, H. Prodrugs as Drug Delivery Systems. Part 42. 2-Hydroxymethlbenzamides as Potential Prodrug Forms for Amines. Int J Pharm 1986; 29:9–18Google Scholar
  67. Nielsen AB, Frydenvang K, Liljefors T, Buur A, and Larsen C. Assessment of the Combined Approach of N-alkylation and Salt Formation to Enhance Aqueous Solubility of Tertiary Amines Using Bupivacaine as a Model Drug. Eur J Pharm Sci 2005; 24:85–93PubMedGoogle Scholar
  68. Okuyama T, Sahn DJ, and Schmir GL. Hydrolysis of Imidate Esters Derived from Weakly Basic Amines. II. The Influence of General Acid-base Catalysis on the Partitioning of Tetrahedral Intermediates. J Am Chem Soc 1973; 95:2345–2352PubMedGoogle Scholar
  69. Orlowski M, and Wilk S. Kidney as a Site of Uptake and Metabolism of gamma-Glutamyl Compounds. Curr Probl Clin Biochem 1977; 8:66–72PubMedGoogle Scholar
  70. Pitman IH. Pro-Drugs of Amides, Imides, and Amines. Med Res Rev 1981; 1:189–214PubMedGoogle Scholar
  71. Pochopin NL, Charman WN, and Stella VJ. Pharmacokinetics of Dapsone and Amino Acid Prodrugs of Dapsone. Drug Metab Dispos 1994; 22:770–775PubMedGoogle Scholar
  72. Raleigh SM, Wanogho E, Burke MD, McKeown SR, and Patterson LH. Involvement of Human Cytochromes P450 (CYP) in the Reductive Metabolism of AQ4N, a Hypoxia Activated Anthraquinone di-N-oxide Prodrug. Int J Radiat Oncol Biol Phys 1998; 42:763–767PubMedGoogle Scholar
  73. Riley RJ, and Workman P. Enzymology of the Reduction of the Potent Benzotriazine-di-N-oxide Hypoxic Cell Cytotoxin SR 4233 (WIN 59075) by NAD(P)H: (Quinone Acceptor) Oxidoreductase (EC Purified from Walker 256 Rat Tumour Cells. Biochem Pharmacol 1992; 43:167–174PubMedGoogle Scholar
  74. Roche EB. Bioreversible Carriers in Drug Design: Theory and Application, Elmsford, NY: Permagon Press; 1987. 292pGoogle Scholar
  75. Safadi M, Oliyai R, and Stella VJ. Phosphoryloxymethyl Carbamates and Carbonates—Novel Water-soluble Prodrugs for Amines and Hindered Alcohols. Pharm Res 1993; 10:1350–1355PubMedGoogle Scholar
  76. Sakuma S, Lu ZR, Kopeckova P, and Kopecek J. Biorecognizable HPMA Copolymer-drug Conjugates for Colon-specific Delivery of 9-Aminocamptothecin. J Control Release 2001; 75:365–379PubMedGoogle Scholar
  77. Sanders JM, Griffin RJ, Burka LT, and Matthews HB. Toxicokinetics of the Cholinomimetic Compound Benzyltrimethylammonium Chloride in the Male Rat and Mouse. Xenobiotica 1995; 25:303–313PubMedGoogle Scholar
  78. Senter PD, Pearce WE, and Greenfield RS. Development of a Drug Release Strategy Based on the Reductive Fragmentation of Benzyl Carbamate Disulfides. J Org Chem 1990; 55:2975–2978Google Scholar
  79. Shan D, Nicolaou MG, Borchardt RT, and Wang B. Prodrug Strategies Based on Intramolecular Cyclization Reactions. J Pharm Sci 1997; 86:765–767PubMedGoogle Scholar
  80. Simpkins JW, and Bodor, N. The Brain Targeted Delivery of Dopamine Using a Redox-based Chemical Delivery System. Adv Drug Deliv Rev 1994; 14:243–249Google Scholar
  81. Sinha VR, and Kumria R. Colonic Drug Delivery: Prodrug Approach. Pharm Res 2001; 18:557–564PubMedGoogle Scholar
  82. Sloan KB. Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. In: Sloan KB. Prodrugs Topical and Ocular Delivery. New York, NY, Marcel Decker, Inc.; 1992:17–116Google Scholar
  83. Sloan KB, and Koch SA. Effect of Nucleophilicity and Leaving Group Ability on the SN2 Reactions of Amines with (Acyloxy)alkyl alpha-Halides: A Product Distribution Study. J Org Chem 1983; 48:635–640Google Scholar
  84. Smith PJ, Blunt NJ, Desnoyers R, Giles Y, and Patterson LH. DNA Topoisomerase II-dependent Cytotoxicity of Alkylaminoanthraquinones and their N-oxides. Cancer Chemother Pharmacol 1997; 39:455–461PubMedGoogle Scholar
  85. Stark H, Krause M, Rouleau A, Garbarg M, Schwartz JC, and Schunack W. Enzyme-catalyzed Prodrug Approaches for the Histamine H3-receptor Agonist (R)-alpha-Methylhistamine. Bioorg Med Chem 2001; 9:191–198PubMedGoogle Scholar
  86. Sykes BM, Atwell GJ, Hogg A, Wilson WR, O’Connor CJ, and Denny WA. NSubstituted 2-(2,6-Dinitrophenylamino)propanamides: Novel Prodrugs that Release a Primary Amine via Nitroreduction and Intramolecular Cyclization. J Med Chem 1999; 42:346–355PubMedGoogle Scholar
  87. Taatjes DJ, Gaudiano G, Resing K, and Koch TH. Alkylation of DNA by the Anthracycline, Antitumor Drugs Adriamycin and Daunomycin. J Med Chem 1996; 39:4135–4138PubMedGoogle Scholar
  88. Tercel M, Wilson WR, and Denny WA. Nitrobenzyl Mustard Quaternary Salts: A New Class of Hypoxia-selective Cytotoxins Showing Very High In Vitro Selectivity. J Med Chem 1993; 36:2578–2579PubMedGoogle Scholar
  89. Tercel M, Lee AE, Hogg A, Anderson RF, Lee HH, Siim BG, Denny WA, and Wilson WR. Hypoxia-selective Antitumor Agents. 16. Nitroarylmethyl Quaternary Salts as Bioreductive Prodrugs of the Alkylating Agent Mechlorethamine. J Med Chem 2001; 44:3511–3522PubMedGoogle Scholar
  90. Testa B, and Mayer JM. Design of Intramolecularly Activated Prodrugs. Drug Metab Rev 1998; 30:787–807PubMedGoogle Scholar
  91. Testa B., and Mayer JM. Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry and Enzymology, Weinheim, Germany, Wiley-VCH; 2003. 780pGoogle Scholar
  92. Tsuji A, and Yamana T. Kinetic Approach to the Development in beta-Lactam Antibiotics. II. Prodrug. (I). Simultaneous Determination of Hetacillin and Ampicillin, and its Application to the Stability of Hetacillin in Aqueous Solutions. Chem Pharm Bull (Tokyo) 1974; 22:2434–2443Google Scholar
  93. Tsukamoto Y, Kato Y, Ura M, Horii I, Ishitsuka H, Kusuhara H, and Sugiyama Y. A Physiologically Based Pharmacokinetic Analysis of Capecitabine, A Triple Prodrug of 5-FU, in Humans: The Mechanism for Tumor-Selective Accumulation of 5-FU. Pharm Res 2001; 18:1190–1202PubMedGoogle Scholar
  94. Vinogradova ND, Kuznetsov SG, and Chigareva SM. Quaternary Ammonium Salts with Labile N+-C Bonds as Drug Precursors. Khim Farm Zh 1980; 14:41–47Google Scholar
  95. Walko CM, and Lindley C. Capecitabine: A Review. Clin Ther 2005; 27:23–44PubMedGoogle Scholar
  96. Wang B, Zhang H, Zheng A, and Wang W. Coumarin-based Prodrugs. Part 3: Structural Effects on the Release Kinetics of Esterase-sensitive Prodrugs of Amines. Bioorg Med Chem 1998; 6:417–426PubMedGoogle Scholar
  97. Wilk S, Mizoguchi H, and Orlowski M. gamma-Glutamyl dopa: A Kidney-specific Dopamine Precursor. J Pharmacol Exp Ther 1978; 206:227–232PubMedGoogle Scholar
  98. Wilson IB, Harrison MA, and Ginsburg S. Wilson IB, Harrison MA, and Ginsburg S. Carbamyl Derivatives of Acetylcholinesterase. Acetylcholinesterase. J Biol Chem 1961; 236:1498–1500PubMedGoogle Scholar
  99. Wiwattanapatapee R, Lomlim L, and Saramunee K. Dendrimers Conjugates for Colonic Delivery of 5-Aminosalicylic acid. J Control Release 2003; 88:1–9PubMedGoogle Scholar
  100. Wong BK, DeFeo-Jones D, Jones RE, Garsky VM, Feng DM, Oliff A, Chiba M, Ellis JD, and Lin JH. PSA-specific and Non-PSA-specific Conversion of a PSA-targeted Peptide Conjugate of Doxorubicin to Its Active Metabolites. Drug Metab Dispos 2001; 29:313–318PubMedGoogle Scholar
  101. Worms P, Depoortere H, Durand A, Morselli PL, Lloyd KG, and Bartholini G. gamma-Aminobutyric Acid (GABA) Receptor Stimulation. I. Neuropharmacological Profiles of Progabide (SL 76002) and SL 75102, with Emphasis on Their Anticonvulsant Spectra. J Pharm Exp Ther 1982; 220:660–671Google Scholar
  102. Zera RT, and Nagasawa HT. N-Acetyl-DL-penicillamine and Acetaminophen Toxicity in Mice. J Pharm Sci 1980; 69:1005–1006PubMedGoogle Scholar
  103. Zhu L, Kumar V, and Banker GS. Examination of Oxidized Cellulose as a Macromolecular Prodrug Carrier: Preparation and Characterization of an Oxidized Cellulose-Phenylpropanolamine Conjugate. Int J Pharm 2001; 223:35–47PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2007

Authors and Affiliations

  • Jeffrey P. Krise
    • 1
  • Reza Oliyai
    • 2
  1. 1.Department of Pharmaceutical ChemistryThe University of KansasLawrence
  2. 2.Gilead PharmaceuticalsFoster City

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