Iron chelator chemistry

Advances in Experimental Medicine and Biology

Volumn 509, Issue , 2003, Pages 141-166

  Liu, Zu D ^a   Liu, Ding Y ^a   Hider, Robert C ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CARBOXYLIC ACID DERIVATIVE; CATECHOL; DEFEROXAMINE; HYDROXAMIC ACID; IRON CHELATING AGENT; IRON COMPLEX; LIGAND; N,N' BIS(2 HYDROXYBENZYL)ETHYLENEDIAMINE N,N' DIACETIC ACID; PENTETIC ACID; PYRIDINOL; SIDEROPHORE; TRIAZOLE DERIVATIVE; IRON;

BINDING AFFINITY; CHONDROPATHY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG STABILITY; ENZYME INHIBITION; HUMAN; HYDROPHILICITY; IRON CHELATION; IRON OVERLOAD; LIGAND BINDING; LIPOPHILICITY; MOLECULAR WEIGHT; NEUROTOXICITY; OXIDATION REDUCTION REACTION; PRIORITY JOURNAL; REVIEW; THERMODYNAMICS; CHEMICAL STRUCTURE; CHEMISTRY; LIPID METABOLISM; METABOLISM;

DRUG DESIGN; HUMANS; IRON; IRON CHELATING AGENTS; IRON OVERLOAD; LIGANDS; LIPID METABOLISM; MOLECULAR STRUCTURE; MOLECULAR WEIGHT;

EID: 0042810744     PISSN: 00652598     EISSN: None     Source Type: Book Series    
DOI: None     Document Type: Review

References (113)

1. Hershko C, Konijn AM, Link G. Iron chelators for thalasaemia. Br J Haematol 1998; 101: 399-406.
2. Martell AE, Smith RM. Critical stability constant. Vol. 1-6. London: Plenum Press, 1974-1989.
3. Harris DC, Aisen P. Facilitation of Fe(II) autoxidation by Fe(III) complexing agents. Biochim Biophys Acta 1973; 329: 156-158.
4. Raymond KN, Muller G, Matzanke BF. Complexation of iron by siderophores: A review of their solution and structural chemistry and biological function. Top Curr Chem 1984; 58: 49-102.
5. 3+ values. Transfus Sci 2000; 23: 201-209.
6. Hider RC, Mohd-Nor AR, Silver J, Morrison IEG, Rees LVC. Model compounds for microbial iron-transport compounds. Part 1. Solution chemistry and mössbauer study of iron(II) and iron(III). Complexes from phenolic and catecholic system. J Chem Soc Dalton Trans 1981; 2: 609-622.
7. Hider RC, Hall AD. Clinically useful chelators of tripositive elements. Prog Med Chem 1991; 28: 41-173.
8. Pippard MJ, Jackson MJ, Hoffman K, Petrou M, Model CB. Iron chelation using subcutaneous infusion of diethyl triaminopentaacetic acid (DTPA). Scand J Haem. 1986; 36: 466-472.
9. 3+. J Inorg Biochem 1986; 28: 181-187.
10. Pierre JL, Gautier-Luneau I. Iron and citric acid: A fuzzy chemistry of ubiquitous biological relevance. Biometals 2000; 13: 91-96.
11. Spiro TG, Bates G, Saltman P. The hydrolytic polymerisation of ferric citrate II. The influence of excess citrate. J Am Chem Soc 1967; 89: 5559-5562.
12. Strouse J, Layten SW, Strouse CE. Structural studies of transition metal complexes of triionized and tetraionized citrate. Models or the coordination of the citrate ion to transition metal ions in solutions and at the active site of aconitase. J Am Chem Soc 1977; 99: 562-572.
13. Meiwes J, Fiedler HP, Haag H, Zahner H, Konetschnyrapp S, Jung G. Isolation and characterization of Staphyloferrin A: A compound with siderophore activity from Staphylococcus hyicus DSM-20459. FEMS Microbiol Lett 1990; 67: 201-205.
14. Thicken A, Winkelmann G. Rhizoferrin - A complexone type siderophore of the Mucorales and Entomophthorales (Zygomycetes). FEMS Microbiol Lett 1992; 94: 37-42.
15. Tilbrook GS, Hider RC. Iron Chelators for clinical use. In: Sigel A, Sigel H, eds. Metal Irons in Biological Systems. Vol. 35: Iron Transport and Storage in Microorganisms, Plants and Animals. New York: Marcel Dekker, 1998:691-730.
16. Florence AT, Attwood D. Physicochemical Principles of Pharmacy. 2nd. ed. London: Macmillan, 1988
17. Holander D, Ricketts D, Boyd CAR. Importance of probe molecular geometry in determining intestinal permeability. Can J Gastroenterol 1988; 2: 35A-38A.
18. Fagerholm U; Nilsson D; Knutson L; Lennemas H. Jejunal permeability in humans in vivo and rats in situ: Investigation of molecular size selectivity and solvent drag. Acta Physiol Scand 1999; 165: 315-324.
19. Travis S, Menzies I. Intestinal permeability: functional assessment and significance. Clin Sci 1992; 82: 471-488.
20. 51Cr-labelled ethylenediaminetetra-acetate, L-rhamnose and polyethyleneglycol 500 as probe markers for assessment in vivo of human intestinal permeability. Clin Sci 1986; 71: 71-80.
21. Kim M. Absorption of polyethylene glycol oligomers (330-1122 Da) is greater in the jejunum than in the ileum of rats. J Nutr 1996; 126: 2172-2178.
22. Yokel RA, Fredenburg AM, Meurer KA, Skinner TL. Influence of lipophilicity on the bioavailability and disposition of orally active 3-hydroxypyridin-4-one metal chelators. Drug Metab Dispo 1995; 23: 1178-1180.
23. Porter JB, Huehns ER, Hider RC. The development of iron chelating drugs. Bailliere's Clin Haematol 1989; 2: 257-292.
24. Pippard MJ, Callender ST, Weatherall DJ. Intensive iron-chelation therapy with desferrioxamine in iron-loading anaemias. Clin Sci Mol Med 1978; 54: 99-106.
25. O'Halloran TV. Transition-metals in control of gene-expression. Science 1993; 261: 715-725.
26. Rae TD; Schmidt PJ; Pufahl RA; Culotta VC; O'Halloran TV. Undetectable intracellular free copper: The requirement of a copper chaperone for superoxide dismutase. Science 1999; 284: 805-808.
27. Singh S, Khodr H, Taylor MI, Hider RC. Therapeutic iron chelators and their potential side-effects. Biochem Soc Symp 1995; 61: 127-137.
28. Hider RC, Kayyli R, Evans P. The production of hydroxyl radicals by Deferiprone-iron compounds under physiological conditions. Blood 1999; 94(suppl):406A-406A.
29. Lippard SJ, Berg JM. Principles of Bioinorganic Chemistry. California: University Science Books, 1994.
30. Britovsek GJP, Gibson VC, Wass DF. The search for new-generation olefin polymerization catalysts: Life beyond metallocenes. Angew Chem Int Ed 1999; 38: 428-447.
31. Hider RC. Potential protection from toxicity by oral iron chelators. Toxicol Lett 1995; 82-3: 961-967.
32. Hider RC, Singh S, Porter JB. Iron chelating agents with clinical potential. Proc Roy Soc Edin 1992; 99B: 137-168.
33. Abeysinghe RD, Robert PJ, Cooper CE, MacLean KH, Hider RC, Porter JB. The environment of the lipoxygenase iron binding site explored with novel hydroxypyridinone iron chelators. J Biol Chem 1996; 271: 7965-7972.
34. Liu ZD, Kayyali RS, Hider RC, Theobald AE. Design, synthesis, and evaluation of novel 2-substituted 3-hydroxypyridin-4-ones: Structure-activity investigation of metalloenzyme inhibition by iron chelators. J Med Chem, in press.
35. Liu ZD, Lockwood M, Rose S, Theobald AE, Hider RC. Structure-activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase. Biochem Pharmacol. 2001; 61: 285-290.
36. Cooper CE, Lynagh GR, Hoyes KP, Hider RC, Cammack R, Porter JB. The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J Biol Chem 1996; 271: 20291-20299.
37. Levin VA. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 1980; 23: 682-684.
38. Oldendorf WH. Lipid solubility and drug penetration of the blood brain barrier. Proc Soc Expt Bio Med 1974; 147: 813-816.
39. Habgood MD, Liu ZD, Dehkordi LS, Khodr HH, Abbott J, Hider RC. Investigation into the correlation between the structure of hydroxypyridinones and blood-brain barrier permeability. Biochem Pharmacol 1999; 57: 1305-1310.
40. Hershko C, Grady RW, Cerami A. Mechanism of iron chelation in the hypertransfused rat: definition of two alternative pathways of iron mobilisation. J Lab Clin Med 1978; 92: 144-149.
41. Summers MR, Jacobs A, Tudway D, Perera P, Ricketts C. Studies in desferrioxamine and ferrioxamine metabolism in normal and iron-loaded subjects. Br J Haematol 1979; 42: 547-555.
42. Porter JB, Jawson MC, Huehns ER, East CA, Hazell JWP. Desferrioxamine toxicity: Evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. Br J Haematol 1989; 73: 403-405.
43. Freedman MH, Grisaru D, Olivieri NF, MacLusky I, Thorner PS. Pulmonary syndrome in patients with thalassemia major receiving intravenous deferoxamine infusions. Am J Dis Child 1990; 144: 565-569.
44. Olivieri NF, Buncic JR, Chew E, Gallant T, Harrison RV, Keenan N, Logan W, Mitchell D, Ricci G, Skarf B. Visual and auditory neurotoxicity in patients receiving subcutaneous desferrioxamine infusions. New Engl J Med 1986; 314: 869-873.
45. Olivieri NF, Harris J, Koren G, Khattak S, Freedman MH, Templeton DM, Bailey JD, Reilly BJ. Growth failure and bony changes induced by deferoxamine. Am J Pediatr Hematol Oncol 1992; 14: 48-56.
46. Peter HH. Industrial aspects of iron chelators: Pharmaceutical application. In: Spik G, Montreuil J, Crichton RR, Mazurier J, eds. Proteins of Iron Storage and Transport. Amsterdam: Elsevier, 1985:293-303.
47. Fechtig B, Peter H. New O-acylhydroxamic acid derivatives. International Patent WO 8603745, 1984.
48. Bergeron RJ, Wiegand J, McManis JS, Perumal PT. Synthesis and biological evaluation of hydroxamate-based iron chelators. J Med Chem 1991; 34:3182-3187.
49. Bergeron RJ, Liu Z, McManis JS, Wiegand J. Structural alterations in desferrioxamine compatible with iron clearance in animals. J Med Chem 1992; 35:4739-4744.
50. Jackson MJ, Brenton DP, Modell B. DTPA in the management of iron overload in thalassaemia. J Inher Met Dis 1983; 6(suppl 2):97-98.
51. Bannerman RM, Callender ST, Williams DL. Effect of desferrioxamine and DTPA in iron overload. Br Med J 1962; 2:1573-1577.
52. L'Eplattenier F, Murase I, Martell AE. New multidentate ligands. IV. Chelating tendencies of N,N′-di(2-hydroxybenzyl)ethylenediamine-N, N′-diacetic acid. J Am Chem Soc 1967; 89: 837-843.
53. Martell AE, Motekaitis RJ, Clarke ET. Synthesis of N,N′-di(2- hydroxybenzyl)ethylenediamine-N,N′-diacetic (HBED) derivatives. Can J Chem 1986; 64:449-456.
54. Lau EH, Cerny EA, Wright BJ, Rahman YE. Improvement of iron removal from the reticuloendothelial system by liposome encapsulation of N,N′-bis[2- hydroxybenzyl]-ethylenediamine-N,N′-diacetic acid (HBED) - Comparison with desferrioxamine. J Lab Clin Med 1983; 101: 806-816.
55. Bergeron RJ, Wiegand J, Brittenham GM. HBED: A potential alternative to deferoxamine for iron-chelating therapy. Blood 1998; 91:1446-1452.
56. Peter HH, Bergeron RJ, Streiff RR, Wiegand J. A comparative evaluation of iron chelators in a primate model. In: Bergeron RJ, Brittenham GM, eds. The Development of Iron Chelators for Clinical Use. London: CRC Press, 1993:373-394.
57. Grady RW, Salbe AD, Hilgartner MW, Giardina PJ. Results from phase I clinical trial of HBED. Adv Exp Med Biol 1994; 356: 351-359.
58. Pitt CG, Bao Y, Thompson J, Wani MC, Rosenkrantz H, Metterville J. Esters and lactones of phenolic amino carboxylic acids: Prodrugs for iron chelation. J Med Chem 1986; 29:1231-1237.
59. Gasparini F, Leutert T, Farley DL. N,N′-bis(2-hydroxybenzyl) ethylene-diamine-N,N′-diacetic acid derivatives as chelating agents. International Patent WO 95/16663, 1995.
60. Lowther N, Tomlinson B, Fox R, Faller B, Sergejew T, Donnelly H. Caco-2 cell permeability of a new (hydroxybenzyl)ethylenediamine oral iron chelator: Correlation with physicochemical properties and oral activity. J Pharm Sci 1998; 87: 1041-1045.
61. Faller B, Spanka C, Sergejew T, Tschinke V. Improving the oral bioavailability of the iron chelator HBED by breaking the symmetry of the intramolecular H-bond network. J Med Chem. 2000; 43:1467-1475.
62. Hider RC, Bittel D, Andrews GK. Competition between iron(III)-selective chelators and zinc-finger domains for zinc(II). Biochem Pharmacol 1999; 57:1031-1035.
63. Guterman SK, Morris PM, Tannenberg WJK. Feasibility of enterochelin as an iron-chelating drug: Studies with human serum and a mouse model system. Gen Pharmac 1978; 9:123-127.
64. White DL, Durbin PW, Jeung N, Raymond KN. Specific sequestering agents for the actinides. 26: Synthesis and initial biological testing of polydentate oxohydroxypyridinecarboxylate ligands. J Med Chem 1988; 31:11-18.
65. Xu JD, Kullgren B, Durbin PW, Raymond KN. Specific sequestering agents for the actinides. 28: Synthesis and initial evaluation of multidentate 4-carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone ligands for in vivo plutonium(IV) chelation. J Med Chem 1995; 38:2606-2614.
66. Rai BL, Khodr H, Hider RC. Synthesis, physico-chemical and iron(III)-chelating properties of novel hexadentate 3-hydroxy-2(1H)pyridinone ligands. Tetrahedron 1999; 55:1129-1142.
67. Hahn FN, McMurry TJ, Hugi A, Raymond KN. Coordination chemistry of microbial iron transport. 42: Structural and spectroscopic characterisation of diastereometric Cr(III) and Co(III) complexes of desferrithiocin. J Am Chem Soc 1990; 112: 1854-1860.
68. Anderegg G, Raber M. Metal complex formation of a new siderphore desferrithiocin and of three related ligands. J Chem Soc Chem Commun 1990; 1194-1196.
69. Wolfe LC. Desferrithiocin. Sem Haematol 1990; 27:117-120.
70. Bergeron RJ, Wiegand J, Dionis JB, Egli-Karmakka M, Frei J, Huxley-Tencer A, Peter HH. Evaluation of desferrithiocin and its synthetic analogues as orally effective iron chelators. J Med Chem 1991; 34:2072-2078.
71. Baker E, Peter WH, Jacobs A. Desferrithiocin is an effective iron chelator in vivo and in vitro but ferrithiocin is toxic. Br J Haematol 1992; 81:424-431.
72. Lattmann R, Acklin P. Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators. International Patent WO 97/49395, 1997.
73. Nick HP, Acklin P, Faller B, Jin Y, Lattmann R, Rouan M-C, Sergejew T, Thomas H, Wiegand H, Schnebli HP. A new, potent, orally active iron chelator. In: Badman DG, Bergeron RJ, Brittenham GM, eds. Iron Chelators: New development strategies. Florida: The Saratoga Group. 2000; 311-331.
74. Heinz U, Hegetschweiler K, Acklin P, Faller B, Lattmann R, Schnebli HP. 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid: A novel efficient and selective iron(III) complexing agent. Angew Chem Int Edit 1999; 38:2568-2570.
75. Ryabukhin YI, Shibaeva NV, Kuzharov AS, Korobkova VG, Khokhlov AV, Garnovskii AD. Synthesis and investigation of complex compounds of transition metals with di(o-hydroxyphenyl)-1,2,4-oxadiazole and its 1,2,4-triazole analogs. Sov J Coordinat Chem 1988; 493-499.
76. Hershko C, Avramovici-Grisaru S, Link G, Gelfand L, Sarel S. Mechanism of in vivo iron chelation by pyridoxal isonicotinoyl hydrazone and other imino derivatives of pyridoxal. J Lab Clin Med 1981; 98:99-108.
77. Ponka P, Borova J, Neuwirt J, Fuchs O. Mobilization of iron from reticulocytes. FEBS Lett 1979; 97:317-321.
78. Johnson DK, Pippard MJ, Murphy TB, Rose NJ. An in vivo evaluation of iron-chelating drugs derived from pyridoxal and its analogs. J Pharmacol Exp Ther 1982; 221:399-403.
79. Cikrt M, Ponka P, Necas E, Neuwirt J. Biliary iron excretion in rats following pyridoxal isonicotinoyl hydrazone. Br J Haematol 1980; 45:275-283.
80. Edward JT, Ponka P, Richardson DR. Partition-coefficients of the iron(III) complexes of pyridoxal isonicotinoyl hydrazone and its analogs and the correlation to iron chelation efficacy. Biometals 1995; 8:209-217.
81. Zanninelli G, Glickstein H, Breuer W, Milgram P, Brissot P, Hider RC, Konijn AM, Libman J, Shanzer A, Cabantchik ZI. Chelation and mobilization of cellular iron by different classes of chelators. Mol Pharmacol 1997; 51:842-852.
82. Webb J, Vitolo LM. Pyridoxal isonicotinoyl hydrazone (PIH): A promising new iron chelator. Birth Defects Original article Ser 1988; 23: 63-70.
83. Avramovicigrisaru S, Sarel S, Cohen S, Bauminger RE. The synthesis, crystal and molecular-structure, and oxidation-state of iron complex from pyridoxal isonicotinoyl hydrazone and ferrous sulfate. Israel J Chem 1985; 25:288-292.
84. Balfour JAB, Foster RH. Deferiprone - A review of its clinical potential in iron overload in beta-thalassaemia major and other transfusion-dependent diseases. Drugs 1999; 58:553-578.
85. Brittenham GM. Development of iron-chelating agents for clinical use. Blood 1992; 80:569-574.
86. Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, McClelland RA, Burt AD, Fleming KA. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. New Engl J Med 1998; 339:417-423.
87. Singh S, Epemolu O, Dobbin PS, Tilbrook GS, Ellis BL, Damani LA, Hider RC. Urinary metabolic profiles in man and rat of 1,2-dimethyl-and 1,2-diethyl substituted 3-hydroxypyridin-4-ones. Drug Metab Dispo 1992; 20:256-261.
88. Nathan DG. An orally active iron chelator. New Engl J Med 1995; 332:953-954.
89. Hoffbrand AV, Al-Refaie F, Davis B, Siritanakatkul N, Jackson BFA, Cochrane J, Prescott E, Wonke B. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood 1998; 91:295-300.
90. Kowdley KV, Kaplan MM. Iron-chelation therapy with oral deferiprone - Toxicity or lack of efficacy? New Engl J Med 1998; 339:468-469.
91. Tricta F, Spino M. Iron chelation with oral deferiprone in patients with thalassemia New Engl J Med 1998; 339:1710.
92. Maggio A, Capra M, Ciaccio C, Magnano C, Rizzo M, et al. Evaluation of efficacy of L1 versus desferrioxamine by clinical randomized multicentric study. Blood 1999; 94(suppl): 34B-34B.
93. Cohen AR, Galanello R, Piga A, Gamberini R, DeSanctis V, Tricta F. Deferiprone and neutropenia: Incidence and characteristics in a long-term safety study. Blood 1999; 94(suppl):406A-406A.
94. Porter JB, Morgan J, Hoyes KP, Burke LC, Huehns ER, Hider RC. Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice. Blood 1990; 76:2389-2396
95. Porter JB, Abeysinghe RD, Hoyes KP, Barra C, Huehns ER, Brooks PN, Blackwell MP, Araneta M, Britenham G, Singh S, Dobbin P, Hider RC. Contrasting interspecies efficacy and toxicology of 1,2-diethyl-3-hydroxypyridin-4-one CP94, relates to differing metabolism of the iron chelating site. Br J Haematol 1993; 85:159-168.
96. Porter JB, Singh S, Katherine PH, Epemolu O, Abeysinghe RD, Hider RC. Lessons from preclinical and clinical studies with 1,2-diethyl-3-hydroxypyridin- 4-one, CP94 and related compounds. Adv Expt Med Biol 1994; 356:361-370
97. Bergeron RJ, Streiff RR, Wiegand J, Luchetta G, Creary EA, Peter HH. A comparison of the iron-clearing properties of 1,2-dimethyl-3-hydroxypyrid-4-one, 1,2-diethyl-3-hydroxypyrid-4-one, and Deferoxamine. Blood 1992; 79:1882-1890.
98. Lu SL, Gosriwatana I, Liu DY, Liu ZD, Mallet AI, Hider RC. Biliary and urinary metabolic profiles of 1,2-diethyl-3-hydroxypyridin-4-one (CP94) in the rat. Drug Metab Dispos 2000; 28:873-879.
99. Singh S, Epemolu RO, Ackerman R, Porter JB, Hider RC. Development of 3-hydroxypyridin-4-ones which do not undergo extensive phase II metabolism. 3rd NIH-Sponsored Symposium on The Development of Iron Chelators for Clinical Use. Gainsville, FL, 1992, Abstract: 52.
100. Singh S, Choudhury R, Epemolu RO, Hider RC. Metabolism and pharmacokinetics of 1-(2′-hydroxyethyl)-and 1-(3′-hydroxypropyl)-2- ethyl-3-hydroxypyridin-4-ones in the rat. Eur J Drug Metab Pharmacokinet 1996; 21:33-41
101. Zanninelli G, Choudury R, Loreal O, Guyader D, Lescoat G, Arnaud J, Verna R, Cosson B, Singh S, Hider RC, Brissot P. Novel orally active iron chelators (3-hydroxypyridin-4-ones) enhance the biliary excretion of plasma non-transferrin-bound iron in rats. J Hepatol 1997; 27:176-184.
102. Rai BL, Dekhordi LS, Khodr H, Jin Y, Liu Z, Hider RC. Synthesis, physicochemical properties and evaluation of N-substituted-2-alkyl-3-hydroxy- 4(1H)-pyridinones. J Med Chem 1998; 41:3347-3359
103. 59Fe-ferritin loaded rat model. Biochem Pharmacol 1999; 57:559-566.
104. Rai BL, Liu ZD, Liu DY, Lu SL, Hider RC. Synthesis, physicochemical properties and biological evaluation of ester prodrugs of 3-hydroxypyridin-4- ones: Design of orally active chelators with clinical potential. Eur J Med Chem 1999; 34:475-485.
105. Liu ZD, Liu DY, Lu SL, Hider RC. Synthesis, physicochemical properties and biological evaluation of aromatic ester prodrugs of 1-(2′- hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP102): Orally active iron chelators with clinical potential. J Pharm Pharmacol 1999; 51:555-564.
106. Liu ZD, Liu DY, Lu SL, Hider RC. Design, synthesis, and biological evaluation of aromatic ester prodrugs of 1-(3′-hydroxypropyl)-2-methyl-3- hydroxypyridin-4-one (CP41) as orally active iron chelators. ArzneimForsch/Drug Res. 2000; 50 (1):461-470.
107. Choudhury R, Epemolu RO, Rai BL, Hider RC, Singh S. (1997) Metabolism and pharmacokinetics of 1-(2′-trimethylacetoxyethyl)-2-ethyl-3- hydroxypvridin-4-one (CP117) in the rat. Drug Metab Dispo 1997; 25:332-339.
108. Liu DY, Liu ZD, Lu SL, Hider RC. Hydrolytic and metabolic characteristics of the esters of 1-(3′-hydroxypropyl)-2-methyl-3- hydroxypyridin-4-one (CP41), potentially useful iron chelators. Pharmacol Toxicol 2000; 86:228-233.
109. Zbinden P. Hydroxypyridinones. US Patent 5,688,815, 1997.
110. Hider RC, Tilbrook GS, Liu ZD. Novel Orally Active Iron(III) Chelators. International Patent WO 98/54138, 1998.
111. 3+ values. J Med Chem 1999; 42:4814-4823.
112. 3+ values. Bioorgan. Med. Chem., 2001; 9:563-573.
113. Lowther N, Fox P, Faller B, Nick H, Jin Y, Sergejew T, Hirschberg Y, Oberle R, Donnelly H. In vitro and in situ permeability of a 'second generation' hydroxypyridinone oral iron chelator: Correlation with physicochemical properties and oral activity. Pharmaceut Res 1999; 16:434-440.