Inhibition of hypoxia-inducible factor prolyl hydroxylase domain oxygen sensors: Tricking the body into mounting orchestrated survival and repair responses

Journal of Medicinal Chemistry

Volumn 56, Issue 23, 2013, Pages 9369-9402

  Rabinowitz, Michael H ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

AKB 6548; ANTIANEMIC AGENT; CHELATING AGENT; COBALT CHLORIDE; CYCLOOXYGENASE 2; DEFERASIROX; ENZYME INHIBITOR; ERYTHROPOIETIN; FERRITIN; FG 2216; FG 4497; GSK 1278863; HEMOGLOBIN; HEPCIDIN; HYPOXIA INDUCIBLE FACTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 1BETA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; JTZ 951; MOLIDUSTAT; OXYGEN; PLACEBO; PROCOLLAGEN PROLINE 2 OXOGLUTARATE 4 DIOXYGENASE; PROLYL HYDROXYLASE DOMAIN INHIBITOR; PYRIDINE DERIVATIVE; QUINOLINE DERIVATIVE; RECOMBINANT ERYTHROPOIETIN; ROXADUSTAT; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN;

ADENOVIRUS; ALTITUDE; ANEMIA; ANGIOGENESIS; CANCER INHIBITION; CANCER RISK; CARBON NUCLEAR MAGNETIC RESONANCE; CARCINOGENICITY; CELL PROLIFERATION; CELL VIABILITY; CHEMICAL STRUCTURE; CHRONIC INFLAMMATION; CHRONIC KIDNEY DISEASE; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLEAR CELL CARCINOMA; COLITIS; CORONARY ARTERY BYPASS GRAFT; CORONARY ARTERY DISEASE; CRYSTAL STRUCTURE; DIALYSIS; DIARRHEA; DISEASE ASSOCIATION; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG MEGADOSE; DRUG RESEARCH; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; DRUG WITHDRAWAL; ENZYME ACTIVITY; ENZYME INHIBITION; ERYTHROPOIESIS; FERRITIN BLOOD LEVEL; GASTROINTESTINAL DISEASE; GENE MUTATION; GENE PRODUCT; GENETIC TRANSCRIPTION; GENOMICS; GLUCOSE METABOLISM; HEADACHE; HEART MUSCLE REVASCULARIZATION; HEART PROTECTION; HEMANGIOBLASTOMA; HEMOGLOBIN DETERMINATION; HEPATITIS; HIGH THROUGHPUT SCREENING; HUMAN; HYPERTENSION; HYPOXIA; IMMUNITY; IRON CHELATION; IRON METABOLISM; ISCHEMIA; ISCHEMIC HEART DISEASE; ISCHEMIC PRECONDITIONING; KIDNEY CARCINOMA; LETHARGY; LIMB ISCHEMIA; LOW DRUG DOSE; MALE INFERTILITY; MYALGIA; NONHUMAN; OXIDATIVE STRESS; OXYGEN TENSION; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHEOCHROMOCYTOMA; PROTEIN DOMAIN; RECOMMENDED DRUG DOSE; RENAL PROTECTION; REPEATED DRUG DOSE; RESPIRATORY TRACT INFECTION; RETINA TUMOR; REVIEW; SENSOR; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; SURVIVAL; SYNTHESIS; THROMBOEMBOLISM; TISSUE INJURY; TISSUE OXYGENATION; TISSUE REPAIR; TREATMENT INDICATION; TREATMENT OUTCOME; TUMOR GROWTH; TUMOR SUPPRESSOR GENE; VASCULAR DISEASE; VIRUS PARTICLE; WOUND HEALING;

EID: 84890449252     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400386j     Document Type: Review

References (307)

1. Donald, K. W. Oxygen poisoning in man; signs and symptoms of oxygen poisoning Br. Med. J. 1947, 1, 712-717
2. Wolfe, W. G.; DeVries, W. C. Oxygen toxicity Annu. Rev. Med. 1975, 26, 203-217
3. Ward, J. P. T. Oxygen sensors in context Biochim. Biophys. Acta, Bioenerg. 2008, 1777, 1-14
4. Weir, E. K.; Lopez-Barneo, J.; Buckler, K. J.; Archer, S. L. Acute oxygen-sensing mechanisms N. Engl. J. Med. 2005, 353, 2042-2055
5. Schuster, S. J.; Badiavas, E. V.; Costa-Giomi, P.; Weinmann, R.; Erslev, A. J.; Caro, J. Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure Blood 1989, 73, 13-16
6. Maxwell, P. H.; Pugh, C. W.; Ratcliffe, P. J. Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 2423-2427
7. Semenza, G. L. Mechanisms of disease: oxygen sensing, homeostasis, and disease N. Engl. J. Med. 2011, 365, 537-547
8. Wenger, R. H. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression FASEB J. 2002, 16, 1151-1162
9. Wenger, R. H.; Stiehl, D. P.; Camenisch, G. Integration of oxygen signaling at the consensus HRE Sci. STKE 2005, 2005, re12
10. Schofield, C. J.; Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases Nat. Rev. Mol. Cell Biol. 2004, 5, 343-354
11. Mole, D. R.; Blancher, C.; Copley, R. R.; Pollard, P. J.; Gleadle, J. M.; Ragoussis, J.; Ratcliffe, P. J. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts J. Biol. Chem. 2009, 284, 16767-16775
12. Semenza, G. L.; Wang, G. L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation Mol. Cell. Biol. 1992, 12, 5447-5454
13. Semenza, G. L.; Jiang, B.-H.; Leung, S. W.; Passantino, R.; Concordet, J.-P.; Maire, P.; Giallongo, A. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1 J. Biol. Chem. 1996, 271, 32529-32537
14. Semenza, G. L. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology Trends Mol. Med. 2001, 7, 345-350
15. Ratcliffe, P. J. HIF-1 and HIF-2: working alone or together in hypoxia? J. Clin. Invest. 2007, 117, 862-865
16. Kim, J.-w.; Tchernyshyov, I.; Semenza, G. L.; Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia Cell Metab. 2006, 3, 177-185
17. Papandreou, I.; Cairns, R. A.; Fontana, L.; Lim, A. L.; Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption Cell Metab. 2006, 3, 187-197
18. Ho, T. K.; Rajkumar, V.; Ponticos, M.; Leoni, P.; Black, D. C. M.; Abraham, D. J.; Baker, D. M. Increased endogenous angiogenic response and hypoxia-inducible factor-1alpha in human critical limb ischemia J. Vasc. Surg. 2006, 43, 125-133
19. Forsythe, J. A.; Jiang, B.-H.; Iyer, N. V.; Agani, F.; Leung, S. W.; Koos, R. D.; Semenza, G. L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1 Mol. Cell. Biol. 1996, 16, 4604-4613
20. Scortegagna, M.; Ding, K.; Zhang, Q.; Oktay, Y.; Bennett, M. J.; Bennett, M.; Shelton, J. M.; Richardson, J. A.; Moe, O.; Garcia, J. A. HIF-2α regulates murine hematopoietic development in an erythropoietin-dependent manner Blood 2005, 105, 3133-3140
21. Paliege, A.; Rosenberger, C.; Bondke, A.; Sciesielski, L.; Shina, A.; Heyman, S. N.; Flippin, L. A.; Arend, M.; Klaus, S. J.; Bachmann, S. Hypoxia-inducible factor-2α-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization Kidney Int. 2010, 77, 312-318
22. Kapitsinou, P. P.; Liu, Q.; Unger, T. L.; Rha, J.; Davidoff, O.; Keith, B.; Epstein, J. A.; Moores, S. L.; Erickson-Miller, C. L.; Haase, V. H. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia Blood 2010, 116, 3039-3048
23. Rolfs, A.; Kvietikova, I.; Gassmann, M.; Wenger, R. H. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1 J. Biol. Chem. 1997, 272, 20055-20062
24. Uniprot. http://www.uniprot.org/uniprot/P27540 (accessed July 11, 2012).
25. Taylor, B. L.; Zhulin, I. B. PAS domains: internal sensors of oxygen, redox potential, and light Microbiol. Mol. Biol. Rev. 1999, 63, 479-506
26. Wang, G. L.; Jiang, B.-H.; Rue, E. A.; Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 5510-5514
27. Huang, L. E.; Arany, Z.; Livingston, D. M.; Bunn, H. F. Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its α subunit J. Biol. Chem. 1996, 271, 32253-32259
28. Maxwell, P. H.; Wiesener, M. S.; Chang, G.-W.; Clifford, S. C.; Vaux, E. C.; Cockman, M. E.; Wykoff, C. C.; Pugh, C. W.; Maher, E. R.; Ratcliffe, P. J. The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis Nature 1999, 399, 271-276
29. Kamura, T.; Sato, S.; Iwai, K.; Czyzyk-Krzeska, M.; Conaway, R. C.; Conaway, J. W. Activation of HIF1α ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 10430-10435
30. Paltoglou, S.; Roberts, B. J. HIF-1α and EPAS ubiquitination mediated by the VHL tumour suppressor involves flexibility in the ubiquitination mechanism, similar to other RING E3 ligases Oncogene 2007, 26, 604-609
31. Min, J.-H.; Yang, H.; Ivan, M.; Gertler, F.; Kaelin, W. G., Jr.; Pavletich, N. P. Structure of an HIF-1α-pVHL complex: hydroxyproline recognition in signaling Science 2002, 296, 1886-1889
32. Hon, W.-C.; Wilson, M. I.; Harlos, K.; Claridge, T. D. W.; Schofield, C. J.; Pugh, C. W.; Maxwell, P. H.; Ratcliffe, P. J.; Stuart, D. I.; Jones, E. Y. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL Nature 2002, 417, 975-978
33. Goldberg, M. A.; Dunning, S. P.; Bunn, H. F. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein Science 1988, 242, 1412-1415
34. Jaakkola, P.; Mole, D. R.; Tian, Y.-M.; Wilson, M. I.; Gielbert, J.; Gaskell, S. J.; von Kriegsheim, A.; Hebestreit, H. F.; Mukherji, M.; Schofield, C. J.; Maxwell, P. H.; Pugh, C. W.; Ratcliffe, P. J. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation Science 2001, 292, 468-472
35. Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J. M.; Lane, W. S.; Kaelin, W. G., Jr. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing Science 2001, 292, 464-468
36. Bruick, R. K.; McKnight, S. L. A conserved family of prolyl-4- hydroxylases that modify HIF Science 2001, 294, 1337-1340
37. Epstein, A. C. R.; Gleadle, J. M.; McNeill, L. A.; Hewitson, K. S.; O'Rourke, J.; Mole, D. R.; Mukherji, M.; Metzen, E.; Wilson, M. I.; Dhanda, A.; Tian, Y.-M.; Masson, N.; Hamilton, D. L.; Jaakkola, P.; Barstead, R.; Hodgkin, J.; Maxwell, P. H.; Pugh, C. W.; Schofield, C. J.; Ratcliffe, P. J. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation Cell 2001, 107, 43-54
38. Schofield, C. J.; Zhang, Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes Curr. Opin. Struct. Biol. 1999, 9, 722-731
39. Neidig, M. L.; Brown, C. D.; Light, K. M.; Fujimori, D. G.; Nolan, E. M.; Price, J. C.; Barr, E. W.; Bollinger, J. M., Jr.; Krebs, C.; Walsh, C. T.; Solomon, E. I. CD and MCD of CytC3 and taurine dioxygenase: role of the facial triad in α-KG-dependent oxygenases J. Am. Chem. Soc. 2007, 129, 14224-14231
40. Price, J. C.; Barr, E. W.; Tirupati, B.; Bollinger, J. M., Jr.; Krebs, C. The first direct characterization of a high-valent iron intermediate in the reaction of an α-ketoglutarate-dependent dioxygenase: a high-spin Fe(IV) complex in taurine/α-ketoglutarate dioxygenase (TauD) from Escherichia coli Biochemistry 2003, 42, 7497-7508
41. Flashman, E.; Hoffart, L. M.; Hamed, R. B.; Bollinger, J. M., Jr.; Krebs, C.; Schofield, C. J. Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen FEBS J. 2010, 277, 4089-4099
42. Riggs-Gelasco, P. J.; Price, J. C.; Guyer, R. B.; Brehm, J. H.; Barr, E. W.; Bollinger, J. M., Jr.; Krebs, C. EXAFS spectroscopic evidence for an Fe:O unit in the Fe(IV) intermediate observed during oxygen activation by taurine:α-ketoglutarate dioxygenase J. Am. Chem. Soc. 2004, 126, 8108-8109
43. England, J.; Guo, Y.; Van, H. K. M.; Cranswick, M. A.; Rohde, G. T.; Bominaar, E. L.; Munck, E.; Que, L. A more reactive trigonal-bipyramidal high-spin oxoiron(IV) complex with a cis-labile site J. Am. Chem. Soc. 2011, 133, 11880-11883
44. Krebs, C.; Fujimori, D. G.; Walsh, C. T.; Bollinger, J. M., Jr. Non-heme Fe(IV)-oxo intermediates Acc. Chem. Res. 2007, 40, 484-492
45. Chowdhury, R.; McDonough, M. A.; Mecinovic, J.; Loenarz, C.; Flashman, E.; Hewitson, K. S.; Domene, C.; Schofield, C. J. Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases Structure 2009, 17, 981-989
46. Koivunen, P.; Hirsilae, M.; Remes, A. M.; Hassinen, I. E.; Kivirikko, K. I.; Myllyharju, J. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF J. Biol. Chem. 2007, 282, 4524-4532
47. Thirstrup, K.; Christensen, S.; Moller, H. A.; Ritzen, A.; Bergstroem, A.-L.; Sager, T. N.; Jensen, H. S. Endogenous 2-oxoglutarate levels impact potencies of competitive HIF prolyl hydroxylase inhibitors Pharmacol. Res. 2011, 64, 268-273
48. Hirsila, M.; Koivunen, P.; Gunzler, V.; Kivirikko, K. I.; Myllyharju, J. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor J. Biol. Chem. 2003, 278, 30772-30780
49. Pappalardi, M. B.; McNulty, D. E.; Martin, J. D.; Fisher, K. E.; Jiang, Y.; Burns, M. C.; Zhao, H.; Ho, T.; Sweitzer, S.; Schwartz, B.; Annan, R. S.; Copeland, R. A.; Tummino, P. J.; Luo, L. Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites Biochem. J. 2011, 436, 363-369
50. Linke, S.; Hampton-Smith, R. J.; Peet, D. J. Characterization of ankyrin repeat-containing proteins as substrates of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible transcription factor Methods Enzymol. 2007, 435, 61-85
51. Coleman, M. L.; Ratcliffe, P. J. Signalling cross talk of the HIF system: involvement of the FIH protein Curr. Pharm. Des. 2009, 15, 3904-3907
52. Driscoll, M.; Gerstbrein, B. Dying for a cause: invertebrate genetics takes on human neurodegeneration Nat. Rev. Genet. 2003, 4, 181-194
53. Metzen, E.; Berchner-Pfannschmidt, U.; Stengel, P.; Marxsen, J. H.; Stolze, I.; Klinger, M.; Huang, W. Q.; Wotzlaw, C.; Hellwig-Burgel, T.; Jelkmann, W.; Acker, H.; Fandrey, J. Intracellular localization of human HIF-1α hydroxylases: implications for oxygen sensing J. Cell Sci. 2003, 116, 1319-1326
54. Takeda, K.; Ho, V. C.; Takeda, H.; Duan, L.-J.; Nagy, A.; Fong, G.-H. Placental but not heart defects are associated with elevated hypoxia-inducible factor α levels in mice lacking prolyl hydroxylase domain protein 2 Mol. Cell. Biol. 2006, 26, 8336-8346
55. Katschinski, D. M. In vivo functions of the prolyl-4-hydroxylase domain oxygen sensors: direct route to the treatment of anaemia and the protection of ischaemic tissues Acta Physiol. 2009, 195, 407-414
56. Takeda, K.; Cowan, A.; Fong, G.-H. Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system Circulation 2007, 116, 774-781
57. Cioffi, C. L.; Liu, X. Q.; Kosinski, P. A.; Garay, M.; Bowen, B. R. Differential regulation of HIF-1α prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells Biochem. Biophys. Res. Commun. 2003, 303, 947-953
58. Oehme, F.; Ellinghaus, P.; Kolkhof, P.; Smith, T. J.; Ramakrishnan, S.; Hutter, J.; Schramm, M.; Flamme, I. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors Biochem. Biophys. Res. Commun. 2002, 296, 343-349
59. Benita, Y.; Kikuchi, H.; Smith, A. D.; Zhang, M. Q.; Chung, D. C.; Xavier, R. J. An integrative genomics approach identifies hypoxia inducible factor-1 (HIF-1)-target genes that form the core response to hypoxia Nucleic Acids Res. 2009, 37, 4587-4602
60. Oliver, K. M.; Taylor, C. T.; Cummins, E. P. Hypoxia. Regulation of NFκB signalling during inflammation: the role of hydroxylases Arthritis Res. Ther. 2009, 11, 215
61. Ameri, K.; Harris, A. L. Activating transcription factor 4 Int. J. Biochem. Cell Biol. 2008, 40, 14-21
62. Koditz, J.; Nesper, J.; Wottawa, M.; Stiehl, D. P.; Camenisch, G.; Franke, C.; Myllyharju, J.; Wenger, R. H.; Katschinski, D. M. Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor Blood 2007, 110, 3610-3617
63. Wenger, R. H.; Camenisch, G.; Stiehl, D. P.; Katschinski, D. M. HIF prolyl-4-hydroxylase interacting proteins: consequences for drug targeting Curr. Pharm. Des. 2009, 15, 3886-3894
64. Trust for America's Health. http://www.healthyamericans.org/report/88/ (accessed July 11, 2012).
65. Ezzati, M.; Horwitz, M. E. M.; Thomas, D. S. K.; Friedman, A. B.; Roach, R.; Clark, T.; Murray, C. J. L.; Honigman, B. Altitude, life expectancy and mortality from ischaemic heart disease, stroke, COPD and cancers: national population-based analysis of US counties J. Epidemiol. Community Health 2012, 66, e17
66. Faeh, D.; Gutzwiller, F.; Bopp, M. Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland Circulation 2009, 120, 495-501
67. Weinberg, C. R.; Brown, K. G.; Hoel, D. G. Altitude, radiation, and mortality from cancer and heart disease Radiat. Res. 1987, 112, 381-390
68. Iyer, N. V.; Kotch, L. E.; Agani, F.; Leung, S. W.; Laughner, E.; Wenger, R. H.; Gassmann, M.; Gearhart, J. D.; Lawler, A. M.; Yu, A. Y.; Semenza, G. L. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α Genes Dev. 1998, 12, 149-162
69. Compernolle, V.; Brusselmans, K.; Franco, D.; Moorman, A.; Dewerchin, M.; Collen, D.; Carmeliet, P. Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1α Cardiovasc. Res. 2003, 60, 569-579
70. Zhang, H.; Bosch-Marce, M.; Shimoda, L. A.; Tan, Y. S.; Baek, J. H.; Wesley, J. B.; Gonzalez, F. J.; Semenza, G. L. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia J. Biol. Chem. 2008, 283, 10892-10903
71. Kline, D. D.; Peng, Y.-J.; Manalo, D. J.; Semenza, G. L.; Prabhakar, N. R. Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 821-826
72. Cai, Z.; Manalo, D. J.; Wei, G.; Rodriguez, E. R.; Fox-Talbot, K.; Lu, H.; Zweier, J. L.; Semenza, G. L. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury Circulation 2003, 108, 79-85
73. Shimoda, L. A.; Semenza, G. L. HIF and the lung: role of hypoxia-inducible factors in pulmonary development and disease Am. J. Respir. Crit. Care Med. 2011, 183, 152-156
74. Tomita, S.; Ueno, M.; Sakamoto, M.; Kitahama, Y.; Ueki, M.; Maekawa, N.; Sakamoto, H.; Gassmann, M.; Kageyama, R.; Ueda, N.; Gonzalez, F. J.; Takahama, Y. Defective brain development in mice lacking the Hif-1α gene in neural cells Mol. Cell. Biol. 2003, 23, 6739-6749
75. Mastrogiannaki, M.; Matak, P.; Keith, B.; Simon, M. C.; Vaulont, S.; Peyssonnaux, C. HIF-2α, but not HIF-1α, promotes iron absorption in mice J. Clin. Invest. 2009, 119, 1159-1166
76. Compernolle, V.; Brusselmans, K.; Acker, T.; Hoet, P.; Tjwa, M.; Beck, H.; Plaisance, S.; Dor, Y.; Keshet, E.; Lupu, F.; Nemery, B.; Dewerchin, M.; Van, V. P.; Plate, K.; Moons, L.; Collen, D.; Carmeliet, P. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice Nat. Med. 2002, 8, 702-710
77. Scortegagna, M.; Morris, M. A.; Oktay, Y.; Bennett, M.; Garcia, J. A. The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice Blood 2003, 102, 1634-1640
78. Rasbach, K. A.; Gupta, R. K.; Ruas, J. L.; Wu, J.; Naseri, E.; Estall, J. L.; Spiegelman, B. M. PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 21866-21871
79. Bohensky, J.; Terkhorn, S. P.; Freeman, T. A.; Adams, C. S.; Garcia, J. A.; Shapiro, I. M.; Srinivas, V. Regulation of autophagy in human and murine cartilage: hypoxia-inducible factor 2 suppresses chondrocyte autophagy Arthritis Rheum. 2009, 60, 1406-1415
80. Gruber, M.; Hu, C.-J.; Johnson, R. S.; Brown, E. J.; Keith, B.; Simon, M. C. Acute postnatal ablation of Hif-2α results in anemia Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 2301-2306
81. Yamada, N.; Horikawa, Y.; Oda, N.; Iizuka, K.; Shihara, N.; Kishi, S.; Takeda, J. Genetic variation in the hypoxia-inducible factor-1α gene is associated with type 2 diabetes in Japanese J. Clin. Endocrinol. Metab. 2005, 90, 5841-5847
82. Kuo, W.-H.; Shih, C.-M.; Lin, C.-W.; Cheng, W.-E.; Chen, S.-C.; Chen, W.; Lee, Y.-L. Association of hypoxia inducible factor-1α polymorphisms with susceptibility to non-small-cell lung cancer Transl. Res. 2012, 159, 42-50
83. Fu, X. S.; Choi, E.; Bubley, G. J.; Balk, S. P. Identification of hypoxia-inducible factor-Iα (HIF-α) polymorphism as a mutation in prostate cancer that prevents normoxia-induced degradation Prostate 2005, 63, 215-221
84. Vainrib, M.; Golan, M.; Amir, S.; Dang, D. T.; Dang, L. H.; Bar-Shira, A.; Orr-Urtreger, A.; Matzkin, H.; Mabjeesh, N. J. HIF1A C1772T polymorphism leads to HIF-1α mRNA overexpression in prostate cancer patients Cancer Biol. Ther. 2012, 13, 720-726
85. Gu, H. F.; Zheng, X.; Abu, S. N.; Gu, T.; Botusan, I. R.; Sunkari, V. G.; Lokman, E. F.; Brismar, K.; Catrina, S.-B. Impact of the hypoxia-inducible factor-1 α (HIF-1α) Pro582Ser polymorphism on diabetes nephropathy Diabetes Care 2013, 36, 415-421
86. Qin, C.; Cao, Q.; Ju, X.; Wang, M.; Meng, X.; Zhu, J.; Yan, F.; Li, P.; Ding, Q.; Chen, J.; Gu, M.; Zhang, W.; Yin, C.; Zhang, Z. The polymorphisms in the VHL and HIF1A genes are associated with the prognosis but not the development of renal cell carcinoma Ann. Oncol. 2012, 23, 981-989
87. Lee, S. J.; Kim, J. G.; Sohn, S. K.; Chae, Y. S.; Moon, J. H.; Kang, B. W.; Park, J. S.; Park, J. Y.; Choi, G. S. No association of the hypoxia-inducible factor-1α gene polymorphisms with survival in patients with colorectal cancer Med. Oncol. 2011, 28, 1032-1037
88. Konac, E.; Onen, H. I.; Metindir, J.; Alp, E.; Biri, A. A.; Ekmekci, A. An investigation of relationships between hypoxia-inducible factor-1α gene polymorphisms and ovarian, cervical and endometrial cancers Cancer Detect. Prev. 2007, 31, 102-109
89. Morris, M. R.; Hughes, D. J.; Tian, Y.-M.; Ricketts, C. J.; Lau, K. W.; Gentle, D.; Shuib, S.; Serrano-Fernandez, P.; Lubinski, J.; Wiesener, M. S.; Pugh, C. W.; Latif, F.; Ratcliffe, P. J.; Maher, E. R. Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma Anticancer Res. 2009, 29, 4337-4343
90. McMullin, M. F. HIF pathway mutations and erythrocytosis Expert Rev. Hematol. 2010, 3, 93-101
91. Furlow, P. W.; Percy, M. J.; Sutherland, S.; Bierl, C.; McMullin, M. F.; Master, S. R.; Lappin, T. R. J.; Lee, F. S. Erythrocytosis-associated HIF-2α mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline J. Biol. Chem. 2009, 284, 9050-9058
92. Imamura, T.; Kikuchi, H.; Herraiz, M.-T.; Park, D.-Y.; Mizukami, Y.; Mino-Kenduson, M.; Lynch, M. P.; Rueda, B. R.; Benita, Y.; Xavier, R. J.; Chung, D. C. HIF-1α and HIF-2α have divergent roles in colon cancer Int. J. Cancer 2009, 124, 763-771
93. Kaelin, W. G., Jr. von Hippel-Lindau disease Annu. Rev. Pathol.: Mech. Dis. 2007, 2, 145-173
94. Kapitsinou, P. P.; Haase, V. H. The VHL tumor suppressor and HIF: insights from genetic studies in mice Cell Death Differ. 2008, 15, 650-659
95. Ma, W.; Tessarollo, L.; Hong, S.-B.; Baba, M.; Southon, E.; Back, T. C.; Spence, S.; Lobe, C. G.; Sharma, N.; Maher, G. W.; Pack, S.; Vortmeyer, A. O.; Guo, C.; Zbar, B.; Schmidt, L. S. Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene Cancer Res. 2003, 63, 5320-5328
96. Haase, V. H.; Glickman, J. N.; Socolovsky, M.; Jaenisch, R. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 1583-1588
97. Knudson, A. G. Antioncogenes and human cancer Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 10914-10921
98. Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics Oncogene 2010, 29, 625-634
99. Kaelin, W. G., Jr. The von Hippel-Lindau tumor suppressor protein: O2 sensing and cancer Nat. Rev. Cancer 2008, 8, 865-873
100. Sergeyeva, A.; Gordeuk, V. R.; Tokarev, Y. N.; Sokol, L.; Prchal, J. F.; Prchal, J. T. Congenital polycythemia in chuvashia Blood 1997, 89, 2148-2154
101. Ang, S. O.; Chen, H.; Hirota, K.; Gordeuk, V. R.; Jelinek, J.; Guan, Y.; Liu, E.; Sergueeva, A. I.; Miasnikova, G. Y.; Mole, D.; Maxwell, P. H.; Stockton, D. W.; Semenza, G. L.; Prchal, J. T. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia Nat. Genet. 2002, 32, 614-621
102. Pastore, Y. D.; Jelinek, J.; Ang, S.; Guan, Y.; Liu, E.; Jedlickova, K.; Krishnamurti, L.; Prchal, J. T. Mutations in the VHL gene in sporadic apparently congenital polycythemia Blood 2003, 101, 1591-1595
103. Takeda, K.; Aguila, H. L.; Parikh, N. S.; Li, X.; Lamothe, K.; Duan, L.-J.; Takeda, H.; Lee, F. S.; Fong, G.-H. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins Blood 2008, 111, 3229-3235
104. Percy, M. J.; Zhao, Q.; Flores, A.; Harrison, C.; Lappin, T. R. J.; Maxwell, P. H.; McMullin, M. F.; Lee, F. S. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 654-659
105. Percy, M. J.; Furlow, P. W.; Beer, P. A.; Lappin, T. R. J.; McMullin, M. F.; Lee, F. S. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove Blood 2007, 110, 2193-2196
106. Ladroue, C.; Carcenac, R.; Leporrier, M.; Gad, S.; Le, H. C.; Galateau-Salle, F.; Feunteun, J.; Pouyssegur, J.; Richard, S.; Gardie, B. PHD2 mutation and congenital erythrocytosis with paraganglioma N. Engl. J. Med. 2008, 359, 2685-2692
107. Astuti, D.; Ricketts, C. J.; Chowdhury, R.; McDonough, M. A.; Gentle, D.; Kirby, G.; Schlisio, S.; Kenchappa, R. S.; Carter, B. D.; Kaelin, W. G., Jr.; Ratcliffe, P. J.; Schofield, C. J.; Latif, F.; Maher, E. R. Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility Endocr.-Relat. Cancer 2011, 18, 73-83
108. Novartis. http://www.google.com/url?sa=t&rct=j&q=&esrc= s&source=web&cd=1&sqi=2&ved=0CB8QFjAA&url=http%3A%2F%2Fwww. novartis.com.au%2FDownloadFile.aspx%3Ft%3Dp%26f%3Dexj. pdf%26dateid%3D1294931209000&ei=BpCAUNfOEJLG0AGwpoGgDA&usg= AFQjCNGnFVTAMTyQCu5PXlTDHYupe3EobQ&cad=rja (accessed August 13, 2012).
109. Zhang, Q.; Gu, J.; Li, L.; Liu, J.; Luo, B.; Cheung, H.-W.; Boehm, J. S.; Ni, M.; Geisen, C.; Root, D. E.; Polyak, K.; Brown, M.; Richardson, A. L.; Hahn, W. C.; Kaelin, W. G., Jr.; Bommi-Reddy, A. Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase Cancer Cell 2009, 16, 413-424
110. Feige, E.; Yokoyama, S.; Levy, C.; Khaled, M.; Igras, V.; Lin, R. J.; Lee, S.; Widlund, H. R.; Granter, S. R.; Kung, A. L.; Fisher, D. E. Hypoxia-induced transcriptional repression of the melanoma-associated oncogene MITF Proc. Natl. Acad. Sci. U.S.A. 2011, 108, E924-E933
111. Hsieh, M. M.; Linde, N. S.; Wynter, A.; Metzger, M.; Wong, C.; Langsetmo, I.; Lin, A.; Smith, R.; Rodgers, G. P.; Donahue, R. E.; Klaus, S. J.; Tisdale, J. F. HIF-prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques Blood 2007, 110, 2140-2147
112. Provenzano, R.; Fadda, G.; Bernardo, M.; James, C.; Kochendoerfer, G.; Lee, T.; Nakayama, S.; Neff, T.; Piper, B. A. FG2216, a novel oral HIF-PHI, stimulates erythropoiesis and increases hemoglobin concentration in patients with non-dialysis CK Am. J. Kidney Dis. 2008, 51, B80
113. Besarab, A.; Chernyavskaya, E. N.; Motylev, I.; Shutov, E.; Yampolskiy, A. F.; Kumbar, L. M.; Gurevich, K.; Chan, D. T. M.; Leong, R.; Zhong, M.; Franco, M.; Yu, K.-H. P.; Neff, T. B. Abstracts of Papers, American Society of Nephrology Kidney Week, San Diego, CA, Oct 30-Nov 4, 2012; American Society of Nephrology: Washington, DC; TH-OR096.
114. Muchnik, E.; Kaplan, J. HIF prolyl hydroxylase inhibitors for anemia Expert Opin. Invest. Drugs 2011, 20, 645-656
115. Deshmukh, A.; Patel, J.; Prajapati, A. Ameliorating effect of cobalt chloride on renal failure and glucose lowering effect in diabetic nephropathy induced in uninephrectomized diabetic rat Drugs Ther. Stud. 2012, 2, 20-25
116. Matsumoto, M.; Makino, Y.; Tanaka, T.; Tanaka, H.; Ishizaka, N.; Noiri, E.; Fujita, T.; Nangaku, M. Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats J. Am. Soc. Nephrol. 2003, 14, 1825-1832
117. Hill, P.; Shukla, D.; Tran, M. G. B.; Aragones, J.; Cook, H. T.; Carmeliet, P.; Maxwell, P. H. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury J. Am. Soc. Nephrol. 2008, 19, 39-46
118. Zhang, X.-L.; Yan, Z.-W.; Sheng, W.-W.; Xiao, J.; Zhang, Z.-X.; Ye, Z.-B. Activation of hypoxia-inducible factor-1 ameliorates postischemic renal injury via inducible nitric oxide synthase Mol. Cell. Biochem. 2011, 358, 287-295
119. Song, Y. R.; You, S. J.; Lee, Y.-M.; Chin, H. J.; Chae, D.-W.; Oh, Y. K.; Joo, K. W.; Han, J. S.; Na, K. Y. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney Nephrol., Dial., Transplant. 2010, 25, 77-85
120. Bernhardt, W. M.; Campean, V.; Kany, S.; Juergensen, J.-S.; Weidemann, A.; Warnecke, C.; Arend, M.; Klaus, S.; Guenzler, V.; Amann, K.; Willam, C.; Weisener, M. S.; Eckardt, K.-U. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure J. Am. Soc. Nephrol. 2006, 17, 1970-1978
121. Chanez-Cardenas, M. E.; Espinoza-Rojo, M.; Rivera-Rodriguez, J. A.; Aguilera, P. Pharmacological strategies that affect HIF-1 in the ischemic brain: focus on hydroxylases activity and protein kinase pathways Curr. Signal Transduction Ther. 2011, 6, 237-248
122. Ogle, M. E.; Gu, X.; Espinera, A. R.; Wei, L. Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces ischemic brain injury and requires hypoxia inducible factor-1α Neurobiol. Dis. 2012, 45, 733-742
123. Kido, M.; Du, L.; Sullivan, C. C.; Li, X.; Deutsch, R.; Jamieson, S. W.; Thistlethwaite, P. A. Hypoxia-inducible factor 1-α reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse J. Am. Coll. Cardiol. 2005, 46, 2116-2124
124. Hyvaerinen, J.; Hassinen, I. E.; Sormunen, R.; Maeki, J. M.; Kivirikko, K. I.; Koivunen, P.; Myllyharju, J. Hearts of hypoxia-inducible factor prolyl 4-hydroxylase-2 hypomorphic mice show protection against acute ischemia-reperfusion injury J. Biol. Chem. 2010, 285, 13646-13657
125. Eckle, T.; Koehler, D.; Lehmann, R.; El, K. K. C.; Eltzschig, H. K. Hypoxia-inducible factor-1 is central to cardioprotection Circulation 2008, 118, 166-175
126. Kilian, E. G.; Sadoni, S.; Vicol, C.; Kelly, R.; van, H. K.; Schwaiger, M.; Kupatt, C.; Boekstegers, P.; Pillai, R.; Channon, K.; Hetzer, R.; Reichart, B. Myocardial transfection of hypoxia inducible factor-1alpha via an adenoviral vector during coronary artery bypass grafting. A multicenter phase I and safety study Circ. J. 2010, 74, 916-924
127. Formenti, F.; Beer, P. A.; Croft, Q. P. P.; Dorrington, K. L.; Gale, D. P.; Lappin, T. R. J.; Lucas, G. S.; Maher, E. R.; Maxwell, P. H.; McMullin, M. F.; O'Connor, D. F.; Percy, M. J.; Pugh, C. W.; Ratcliffe, P. J.; Smith, T. G.; Talbot, N. P.; Robbins, P. A. Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2α gain-of-function mutation FASEB J. 2011, 25, 2001-2011
128. Kasivisvanathan, V.; Shalhoub, J.; Lim, C. S.; Shepherd, A. C.; Thapar, A.; Davies, A. H. Hypoxia-inducible factor-1 in arterial disease: a putative therapeutic target Curr. Vasc. Pharmacol. 2011, 9, 333-349
129. Bosch-Marce, M.; Okuyama, H.; Wesley, J. B.; Sarkar, K.; Kimura, H.; Liu, Y. V.; Zhang, H.; Strazza, M.; Rey, S.; Savino, L.; Zhou, Y. F.; McDonald, K. R.; Na, Y.; Vandiver, S.; Rabi, A.; Shaked, Y.; Kerbel, R.; LaVallee, T.; Semenza, G. L. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia Circ. Res. 2007, 101, 1310-1318
130. Karhausen, J.; Furuta, G. T.; Tomaszewski, J. E.; Johnson, R. S.; Colgan, S. P.; Haase, V. H. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis J. Clin. Invest. 2004, 114, 1098-1106
131. Robinson, A.; Keely, S.; Karhausen, J.; Gerich, M. E.; Furuta, G. T.; Colgan, S. P. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition Gastroenterology 2008, 134, 145-155
132. Cummins, E. P.; Seeballuck, F.; Keely, S. J.; Mangan, N. E.; Callanan, J. J.; Fallon, P. G.; Taylor, C. T. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis Gastroenterology 2008, 134, 156-165
133. Hindryckx, P.; De, V. M.; Jacques, P.; Ferdinande, L.; Peeters, H.; Olievier, K.; Bogaert, S.; Brinkman, B.; Vandenabeele, P.; Elewaut, D.; Laukens, D. Hydroxylase inhibition abrogates TNF-α-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD J. Immunol. 2010, 185, 6306-6316
134. Hirota, S. A.; Fines, K.; Jeffrey, N. G.; Traboulsi, D.; Lee, J.; Ihara, E.; Li, Y.; Willmore, W. G.; Chung, D.; Scully, M. M.; Louie, T.; Medlicott, S.; Lejeune, M.; Chadee, K.; Armstrong, G.; Colgan, S. P.; Muruve, D. A.; MacDonald, J. A.; Beck, P. L. Hypoxia-inducible factor signaling provides protection in Clostridium difficile -induced intestinal injury Gastroenterology 2010, 139, 259-269
135. Hart, M. L.; Grenz, A.; Gorzolla, I. C.; Schittenhelm, J.; Dalton, J. H.; Eltzschig, H. K. Hypoxia-inducible factor-1α-dependent protection from intestinal ischemia/reperfusion injury involves ecto-5′-nucleotidase (CD73) and the A2B adenosine receptor J. Immunol. 2011, 186, 4367-4374
136. Marchbank, T.; Mahmood, A.; Harten, S.; Maxwell, P. H.; Playford, R. J. Dimethyloxalyglycine stimulates the early stages of gastrointestinal repair processes through VEGF-dependent mechanisms Lab. Invest. 2011, 91, 1684-1694
137. Thangarajah, H.; Vial, I. N.; Grogan, R. H.; Yao, D.; Shi, Y.; Januszyk, M.; Galiano, R. D.; Chang, E. I.; Galvez, M. G.; Glotzbach, J. P.; Wong, V. W.; Brownlee, M.; Gurtner, G. C. HIF-1α dysfunction in diabetes Cell Cycle 2010, 9, 75-79
138. Botusan, I. R.; Sunkari, V. G.; Savu, O.; Catrina, A. I.; Gruenler, J.; Lindberg, S.; Pereira, T.; Ylae-Herttuala, S.; Poellinger, L.; Brismar, K.; Cartrina, S.-B. Stabilization of HIF-1α is critical to improve wound healing in diabetic mice Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 19426-19431
139. Thangarajah, H.; Yao, D.; Chang, E. I.; Shi, Y.; Jazayeri, L.; Vial, I. N.; Galiano, R. D.; Du, X.-L.; Grogan, R.; Galvez, M. G.; Januszyk, M.; Brownlee, M.; Gurtner, G. C. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13505-13510
140. Rajagopalan, S.; Olin, J.; Deitcher, S.; Pieczek, A.; Laird, J.; Grossman, P. M.; Goldman, C. K.; McEllin, K.; Kelly, R.; Chronos, N. Use of a vonstitutively sctive hypoxia-inducible gactor-1α transgene as a therapeutic dtrategy in no-option critical limb ischemia patients Circulation 2007, 115, 1234-1243
141. McDonough, M. A.; Li, V.; Flashman, E.; Chowdhury, R.; Mohr, C.; Lienard, B. M. R.; Zondlo, J.; Oldham, N. J.; Clifton, I. J.; Lewis, J.; McNeill, L. A.; Kurzeja, R. J. M.; Hewitson, K. S.; Yang, E.; Jordan, S.; Syed, R. S.; Schofield, C. J. Cellular oxygen sensing: crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2) Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 9814-9819
142. Klaus, S. J.; Molineaux, C. J.; Neff, T. B.; Guenzler-Pukall, V.; Lansetmo, P. I.; Seeley, T. W.; Stephenson, R. C. Use of Hypoxia-Inducible Factor α (HIFα) Stabilizers for Enhancing Erythropoiesis. WO2004108121A1, 2004; CAplus AN 2004:1074114.
143. Warshakoon, N. C.; Wu, S.; Boyer, A.; Kawamoto, R.; Sheville, J.; Renock, S.; Xu, K.; Pokross, M.; Zhou, S.; Winter, C.; Walter, R.; Mekel, M.; Evdokimov, A. G. Structure-based design, synthesis, and SAR evaluation of a new series of 8-hydroxyquinolines as HIF-1α prolyl hydroxylase inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 5517-5522
144. Rosen, M. D.; Venkatesan, H.; Peltier, H. M.; Bembenek, S. D.; Kanelakis, K. C.; Zhao, L. X.; Leonard, B. E.; Hocutt, F. M.; Wu, X.; Palomino, H. L.; Brondstetter, T. I.; Haugh, P. V.; Cagnon, L.; Yan, W.; Liotta, L. A.; Young, A.; Mirzadegan, T.; Shankley, N. P.; Barrett, T. D.; Rabinowitz, M. H. Benzimidazole-2-pyrazole HIF prolyl 4-hydroxylase inhibitors as oral erythropoietin secretagogues ACS Med. Chem. Lett. 2010, 1, 526-529
145. Kivirikko, K. I.; Myllylae, R. Posttranslational enzymes in the biosynthesis of collagen: intracellular enzymes Methods Enzymol. 1982, 82, 245-304
146. Hashimoto, T.; Yamada, Y. Hyoscyamine 6β-hydroxylase, a 2-oxoglutarate-dependent dioxygenase, in alkaloid-producing root cultures Plant Physiol. 1986, 81, 619-625
147. De, C. E.; Chan, F.; Balsevich, J.; De, L. V. Isolation and characterization of a 2-oxoglutarate dependent dioxygenase involved in the second-to-last step in vindoline biosynthesis Plant Physiol. 1990, 94, 1323-1329
148. 14C]succinate: application to prolyl 4-hydroxylase Anal. Biochem. 1990, 184, 291-297
149. Hewitson, K. S.; Schofield, C. J.; Ratcliffe, P. J. Hypoxia-inducible factor prolyl-hydroxylase: purification and assays of PHD2 Methods Enzymol. 2007, 435, 25-42
150. Wirthner, R.; Balamurugan, K.; Stiehl, D. P.; Barth, S.; Spielmann, P.; Oehme, F.; Flamme, I.; Katschinski, D. M.; Wenger, R. H.; Camenisch, G. Determination and modulation of prolyl-4-hydroxylase domain oxygen sensor activity Methods Enzymol. 2007, 435, 43-60
151. Kanelakis, K. C.; Palomino, H. L.; Li, L.; Wu, J.; Yan, W.; Rosen, M. D.; Rizzolio, M. C.; Trivedi, M.; Morton, M. F.; Yang, Y.; Venkatesan, H.; Rabinowitz, M. H.; Shankley, N. P.; Barrett, T. D. Characterization of a robust enzymatic assay for inhibitors of 2-oxoglutarate-dependent hydroxylases J. Biomol. Screening 2009, 14, 627-635
152. Ehrismann, D.; Flashman, E.; Genn, D. N.; Mathioudakis, N.; Hewitson, K. S.; Ratcliffe, P. J.; Schofield, C. J. Studies on the activity of the hypoxia-inducible-factor hydroxylases using an oxygen consumption assay Biochem. J. 2007, 401, 227-234
153. Flashman, E.; Davies, S. L.; Yeoh, K. K.; Schofield, C. J. Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents Biochem. J. 2010, 427, 135-142
154. Maxwell, P. H.; Pugh, C. W.; Ratcliffe, P. J.; Schofield, C. J. Identification, Assay Method, Characterization, Modulators and Therapeutic Use of HIF Prolyl Hydroxylase from Human and C. elegans. WO2002074981A2, 2002; CAplus AN 2002:736425.
155. McKnight, S. L.; Bruick, R. K. An Assay for Human HIF Prolyl Hydroxylase Using a Peptide Substrate, Identification of Human HPH Isoenzymes, and Drug Screening Applications. WO2003028663A2, 2003; CAplus AN 2003:282345.
156. Oehme, F.; Jonghaus, W.; Narouz-Ott, L.; Huetter, J.; Flamme, I. A nonradioactive 96-well plate assay for the detection of hypoxia-inducible factor prolyl hydroxylase activity Anal. Biochem. 2004, 330, 74-80
157. Cho, H.; Park, H.; Yang, E. G. A fluorescence polarization-based interaction assay for hypoxia-inducible factor prolyl hydroxylases Biochem. Biophys. Res. Commun. 2005, 337, 275-280
158. Bex, C.; Knauth, K.; Dambacher, S.; Buchberger, A. A yeast two-hybrid system reconstituting substrate recognition of the von Hippel-Lindau tumor suppressor protein Nucleic Acids Res. 2007, 35, e142/141-e142/149
159. Dao, J. H.; Kurzeja, R. J. M.; Morachis, J. M.; Veith, H.; Lewis, J.; Yu, V.; Tegley, C. M.; Tagari, P. Kinetic characterization and identification of a novel inhibitor of hypoxia-inducible factor prolyl hydroxylase 2 using a time-resolved fluorescence resonance energy transfer-based assay technology Anal. Biochem. 2009, 384, 213-223
160. Vachal, P.; Miao, S.; Pierce, J. M.; Guiadeen, D.; Colandrea, V. J.; Wyvratt, M. J.; Salowe, S. P.; Sonatore, L. M.; Milligan, J. A.; Hajdu, R.; Gollapudi, A.; Keohane, C. A.; Lingham, R. B.; Mandala, S. M.; DeMartino, J. A.; Tong, X.; Wolff, M.; Steinhuebel, D.; Kieczykowski, G. R.; Fleitz, F. J.; Chapman, K.; Athanasopoulos, J.; Adam, G.; Akyuz, C. D.; Jena, D. K.; Lusen, J. W.; Meng, J.; Stein, B. D.; Xia, L.; Sherer, E. C.; Hale, J. J. 1,3,8-Triazaspiro[4.5]decane-2,4-diones as efficacious pan-inhibitors of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) for the treatment of anemia J. Med. Chem. 2012, 55, 2945-2959
161. Broadwater, J. A.; Khine, H. H.; Lin, S.; Schneiderman, R. D. Drug Discovery Assay for Modulators of HIF-Prolyl Hydroxylase Activity. US20100240069A1, 2010; CAplus AN 2010:1190979.
162. Hong, S.; Yum, S.; Ha, N.-C.; Jung, Y. von Hippel-Lindau β-domain-luciferase fusion protein as a bioluminescent hydroxyproline sensor for a hypoxia-inducible factor prolyl hydroxylase assay Anal. Biochem. 2010, 407, 220-225
163. Smirnova, N. A.; Rakhman, I.; Moroz, N.; Basso, M.; Payappilly, J.; Kazakov, S.; Hernandez-Guzman, F.; Gaisina, I. N.; Kozikowski, A. P.; Ratan, R. R.; Gazaryan, I. G. Utilization of an in vivo reporter for high throughput identification of branched small molecule regulators of hypoxic adaptation Chem. Biol. 2010, 17, 380-391
164. Vreugdenhil, G.; Smeets, M.; Feelders, R. A.; van, E. H. G. Iron chelators may enhance erythropoiesis by increasing iron delivery to hematopoietic tissue and erythropoietin response in iron-loading anemia Acta Haematol. 1993, 89, 57-60
165. Rabinowitz, M. H.; Venkatesan, H.; Rosen, M.; Peltier, H.; Woods, C.; Tarantino, K.; Hocutt, F.; Leonard, B.; Zhao, L.; Barrett, T. D.; Palomino, H.; Brondstetter, T.; Wu, X.; Shankley, N. P.; Kanelakis, K.; Haugh, P.; Mirzadegan, T.; Bembenek, S. Abstracts of Papers, 239th National Meeting of the American Chemical Society, San Francisco, CA, March 21-25, 2010; American Chemical Society: Washington, DC, 2010; MEDI-321.
166. Weidmann, K.; Baringhaus, K.-H.; Tschank, G.; Werner, U. Isoquinoline-2-carboxamides as Prolyl-4-hydroxylase inhibitors. DE19746287A1, 1999; CAplus AN 1999:271613.
167. Rendina, A. R.; Orme-Johnson, W. H. Glutamate synthase: the kinetic mechanism of the enzyme from Escherichia coli W Biochemistry 1978, 17, 5388-5393
168. Baader, E.; Burghard, H.; Guenzler-Pukall, V. Preparation of Oxalylamino Acid Derivatives as Proline and Lysine Hydroxylase Inhibitors. DE4015255A1, 1991; CAplus AN 1992:129617.
169. Baader, E.; Tschank, G.; Baringhaus, K.-H.; Burghard, H.; Guenzler, V. Inhibition of prolyl 4-hydroxylase by oxalyl amino acid derivatives in vitro, in isolated microsomes and in embryonic chicken tissues Biochem. J. 1994, 300, 525-530
170. Cunliffe, C. J.; Franklin, T. J.; Hales, N. J.; Hill, G. B. Novel inhibitors of prolyl 4-hydroxylase. 3. Inhibition by the substrate analog N -oxaloglycine and its derivatives J. Med. Chem. 1992, 35, 2652-2658
171. Guenzler-Pukall, V.; Neff, T. B.; Wang, Q.; Arend, M. P.; Flippin, L. A.; Melekhov, A. Stabilization of Hypoxia-Inducible Factor (HIF) alpha. WO2003049686A2, 2003; CAplus AN 2003:472343.
172. Klaus, S. J.; Neff, T. B. Hypoxia Inducible Factor (HIF) Hydroxylase Inhibitors for the Treatment of Anemia. US20060276477A1, 2006; CAplus AN 2006:1286011.
173. Guenzler-Pukall, V.; Wang, Q.; Langsetmo, P. I.; Guo, G. Methods for Reducing Blood Pressure. WO2009058403A1, 2009; CAplus AN 2009:553258.
174. Arend, M. P.; Flippin, L. A.; Guenzler-Pukall, V.; Ho, W.-B.; Turtle, E. D.; Du, X. Preparation of Isoquinolinecarboxamides and Their Use in Mediating Hypoxia Inducible Factor and Increasing Endogenous Erythropoietin. WO2004108681A1, 2004; CAplus AN 2004:1080867.
175. Turtle, E. D.; Flippin, L. A.; Arend, M. P.; Cheng, H. Preparation of Thienopyridine Carboxamides As Hypoxia Inducible Factor (HIF) Modulators. US20060199836A1, 2006; CAplus AN 2006:919505.
176. Arend, M. P.; Flippin, L. A.; Wu, M.; Turtle, E. D.; Ho, W.-B.; Deng, S. Preparation of 1-Cyanoisoquinoline Derivatives as Hypoxia Inducible Factor Hydroxylase Inhibitors. WO2007090068A2, 2007; CAplus AN 2007:874472.
177. Deng, S.; Wu, M.; Turtle, E. D.; Ho, W.-B.; Arend, M. P.; Cheng, H.; Flippin, L. A. Preparation of Pyrrolopyridines and Thiazolopyridines, Particularly N -[(4-Hydroxy-1 H -pyrrolo[2,3- c ]pyridin-5-yl)carbonyl]glycine and N -(7-Hydroxythiazolo[4,5- c ]pyridin-6-yl)carbonyl]glycine Derivatives, as Hypoxia Inducible Factor Hydroxylase Modulators. WO2007115315A2, 2007; CAplus AN 2007:1145598.
178. Zhou, X.; Arend, M. P.; Wu, M.; Flippin, L. A. Preparation of Isothiazole-pyridine Derivatives as Modulators of HIF (Hypoxia Inducible Factor) Activity. WO2009089547A1, 2009; CAplus AN 2009:859439.
179. Ho, W.-B.; Wright, L.; Deng, S.; Turtle, E.; Flippin, L. A. Chromen-3-ylamide Derivatives as Hypoxia Inducible Factor Hydroxylase Inhibitors Useful in the Treatment of Diseases and Preparation Thereof. WO2009100250A1, 2009; CAplus AN 2009:977081.
180. Ho, W.-B.; Wright, L. R.; Turtle, E. D.; Mossman, C.; Flippin, L. A. Preparation of Thiochromenecarbonylaminoacetates as Hypoxia Inducible Factor (HIF) Hydroxylase Inhibitors,. WO2010056767A1, 2010; CAplus AN 2010:628235.
181. Guenzler-Pukall, V.; Klaus, S. J.; Langsetmo, P. I.; Seeley, T. W. Methods of Treating Diabetes Using Heterocyclic Carbonyl Compounds. US8124582B2, 2012; CAplus AN 2012:289969.
182. Chow, F. A.; Klaus, S. J.; Langsetmo, P. I. Methods for Inhibiting T Helper Cell Differentiation. US20100144737A1, 2010; CAplus AN 2010:717637.
183. Klaus, S. J.; Neff, T. B.; Walkinshaw, G.; Chow, A. Methods Using (Hetero)cyclic Carboxamides for the Treatment of Multiple Sclerosis. WO2010024908A1, 2010; CAplus AN 2010:275373.
184. Klaus, S. J.; Milosevic, J.; Neff, T. B.; Schwarz, J.; Walkinshaw, G. Methods for Increasing Neurogenesis. WO2010024911A1, 2010; CAplus AN 2010:274854.
185. Klaus, S. J.; Langsetmo, P. I.; Sirenko, O. Methods Using HIF Prolyl Hydroxylase Inhibitors for Increasing Endothelial Progenitor Cells. WO2009075824A1, 2009; CAplus AN 2009:738967.
186. Seeley, T. W.; Liu, D. Y.; Klaus, S. J. HIF Hydroxylase Activity-Inhibiting Compounds and Methods for Treatment of Chemotherapy-Induced Anemia, US20070292433A1, 2007; CAplus AN 2007:1449086.
187. Klaus, S. J.; Langsetmo, P. I.; Jacob, C. T. Compounds and Methods for Treatment of Stroke. WO2007097929A1, 2007; CAplus AN 2007:964332.
188. Colgan, S. P. Inflammatory Bowel Disease Therapies. WO2009002533A1, 2008; CAplus AN 2009:4022.
189. Seeley, T. W.; Liu, D. Y.; Klaus, S. J. Compounds and Methods for Treatment of Cancer-Related Anemia. US20070293575A1, 2007; CAplus AN 2007:1449464.
190. Seeley, T. A.; Liu, D. Y.; Klauss, S. J. HIF Prolyl Hydroxylase Modifiers and Methods for Treatment of Cancer. WO2006138511A2, 2006; CAplus AN 2006:1357228.
191. Klaus, S. J.; Ratcliffe, P. J. Inhibitors of 2-Oxoglutarate Dioxygenase as gamma Globin Inducers. WO2005011696A1, 2005; CAplus AN 2005:120744.
192. Chai, D.; Colon, M.; Duffy, K. J.; Fitch, D. M.; Tedesco, R.; Zimmerman, M. N. Preparation of N -[(4-Hydroxy-2-oxo-1,2-dihydro-3-quinolinyl)carbonyl] glycine Derivatives as Prolyl Hydroxylase Inhibitors. WO2007038571A2, 2007; CAplus AN 2007:379627.
193. Fitch, D. M.; Colon, M. Preparation of Naphthyridine Derivatives as Prolyl Hydroxylase Inhibitors. WO2007103905A2, 2007; CAplus AN 2007:1033089.
194. Fitch, D. M.; Chai, D. Preparation of Bicyclic Heteroarom. N-Substituted Glycine Derivs. as Prolyl Hydroxylase Inhibitors. WO2007136990A2, 2007; CAplus AN 2007:1361666.
195. Duffy, K. J.; Fitch, D. M.; Jin, J.; Liu, R.; Shaw, A. N.; Wiggall, K. Preparation of N-Substituted Pyrimidine-trione Amino Acid Derivatives as Prolyl Hydroxylase Inhibitors. WO2007150011A2, 2007; CAplus AN 2007:1469947.
196. Shaw, A. N.; Duffy, K. J.; Tedesco, R.; Wiggall, K. Preparation of N-Substituted Pyrimidine-dione Glycine Derivatives as Prolyl Hydroxylase Inhibitors. US20080171756A1, 2008; CAplus AN 2008:857899.
197. Shaw, A. N.; Duffy, K. J.; Miller, W. H.; Myers, A. K.; Zimmerman, M. N. Preparation of 4-Pyridazinylcarbonylglycine Derivatives as Hydroxylase Inhibitors. WO2008089052A2, 2008; CAplus AN 2008:888410.
198. Chai, D. Prolyl Hydroxylase Inhibitors. WO2009039321A1, 2009; CAplus AN 2009:360080.
199. Chai, D.; Fitch, D. M. Prolyl Hydroxylase Inhibitors. WO2009039322A1, 2009; CAplus AN 2009:360305.
200. Chai, D.; Fitch, D. M.; Tedesco, R.; Zimmerman, M. N. Prolyl Hydroxylase Inhibitors. WO2009039323A1, 2009; CAplus AN 2009:364049.
201. Shaw, A. N.; Tedesco, R. Prolyl Hydroxylase Inhibitors, WO2010022307A2, 2010; CAplus AN 2010:238525.
202. Tedesco, R. Pyrimidinedione N-Substituted Glycine Derivative HIF Prolyl Hydroxylase Inhibitors for the Treatment of Anemia and Other Diseases. WO2010025087A1, 2010; CAplus AN 2010:274539.
203. Brackley, J. A., III; Shaw, A. N.; Tedesco, R.; Wang, Y.; Wiggall, K. J.; Yu, H. N -Glycinyl Pyridinedicarboxamide Derivatives as HIF Prolyl Hydroxylase Inhibitors and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Anemia. WO2009158315A1, 2009; CAplus AN 2009:1617944.
204. Shaw, A. N. Prolyl Hydroxylase Inhibitors. WO2009049112A1, 2009; CAplus AN 2009:456505.
205. Fitch, D. M. Preparation of N -[(7-hHydroxyquinolin-8-yl)carbonyl]glycine Derivatives As Prolyl Hydroxylase Inhibitors. WO2009070644A1, 2009; CAplus AN 2009:670896.
206. Colon, M.; Fitch, D. M. Preparation of N -[(6-Hydroxyquinoxalin-5-yl) carbonyl]glycine Derivatives as Prolyl Hydroxylase Inhibitors. WO2009073497A2, 2009; CAplus AN 2009:710007.
207. Chai, D.; Fitch, D. M. Bis-imidazobenzamide Derivatives as Prolyl Hydroxylase Inhibitors for the Treatment of Disease. WO2009134847A1, 2009; CAplus AN 2009:1365828.
208. Chai, D.; Fitch, D. M. Benzimidazole-4-carboxamide Derivatives as Prolyl Hydroxylase Inhibitors. WO2009134850A1, 2009; CAplus AN 2009:1365839.
209. Schulz, M. J.; Adams, G. L.; Brackley, J. A.; Yu, H.; Ghergurovich, J. M.; Sanchez, R. M.; Qu, J.; Burton, G.; Wang, Y. Abstracts of Papers, 240th National Meeting of the American Chemical Society, Boston, MA, August 22-26, 2010; American Chemical Society: Washington, DC, 2010; MEDI-231.
210. Schulz, M. J.; Wang, Y. Prolyl Hydroxylase Inhibitors. WO2010059549A1, 2010; CAplus AN 2010:652417.
211. Gotchev, D. B.; Jin, J.; Wang, Y. Preparation of 4-Oxo-2-thioxo-1,2,3,4- tetrahydro-7-quinazolinecarboxamide Derivatives as Inhibitors of HIF Prolyl Hydroxylase. WO2009086044A1, 2009; CAplus AN 2009:821882.
212. Jin, J.; Schulz, M. J.; Wang, Y. Prolyl Hydroxylase Inhibitors for the Treatment of Disease Such as Anemia. WO2010022308A1, 2010; CAplus AN 2010:238529.
213. Schulz, M. J.; Wang, Y.; Ghergurovich, J. M. Prolyl Hydroxylase Inhibitors. WO2010059555A1, 2010; CAplus AN 2010:652656.
214. Wang, Y.; Yu, H. Prolyl Hydroxylase Inhibitors. WO2010059552A1, 2010; CAplus AN 2010:652466.
215. Evdokimov, A. G.; Kawamoto, R. M.; Boyer, A. S.; Mekel, M. J.; Pokross, M. E.; Walter, R. L. The Crystal Structure of the Complex of Hypoxia Inducible Factor 1α and α-Prolyl Hydroxylase and Its Use in Drug Design. US20080124740A1, 2008; CAplus AN 2008:644835.
216. Warshakoon, N. C.; Wu, S.; Boyer, A.; Kawamoto, R.; Sheville, J.; Renock, S.; Xu, K.; Pokross, M.; Evdokimov, A. G.; Walter, R.; Mekel, M. A novel series of imidazo[1,2- a ]pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 5598-5601
217. Warshakoon, N. C.; Wu, S.; Boyer, A.; Kawamoto, R.; Sheville, J.; Bhatt, R. T.; Renock, S.; Xu, K.; Pokross, M.; Zhou, S.; Walter, R.; Mekel, M.; Evdokimov, A. G.; East, S. Design and synthesis of substituted pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 5616-5620
218. Warshakoon, N. C.; Wu, S.; Boyer, A.; Kawamoto, R.; Renock, S.; Xu, K.; Pokross, M.; Evdokimov, A. G.; Zhou, S.; Winter, C.; Walter, R.; Mekel, M. Design and synthesis of a series of novel pyrazolylpyridines as HIF 1-α prolyl hydroxylase inhibitors Bioorg. Med. Chem. Lett. 2006, 16, 5687-5690
219. Kawamoto, R. M. Preparation of Pyridinylcarboxamide and Phenylcarboxamide Derivatives as Prolyl Hydroxylase Inhibitors and Methods of Use. US20070299086A1, 2007; CAplus AN 2007:1476060.
220. Demetriades, M.; Leung, I. K. H.; Chowdhury, R.; Chan, M. C.; McDonough, M. A.; Yeoh, K. K.; Tian, Y.-M.; Claridge, T. D. W.; Ratcliffe, P. J.; Woon, E. C. Y.; Schofield, C. J. Dynamic combinatorial chemistry employing boronic acids/boronate esters leads to potent oxygenase inhibitors Angew. Chem., Int. Ed. 2012, 51, 6672-6675
221. Akebia. http://www.akebia.com/about-us.html (accessed October 12, 2012).
222. Akebia. http://www.akebia.com/products.html (accessed August 13, 2012).
223. Gardner, J. H.; Shalwitz, R. Prolyl Hydroxylase Inhibitors. WO2011057115A1, 2011; CAplus AN 2011:594227.
224. Shalwitz, R.; Gardner, J. H. Methods for Increasing the Stabilization of HIF-1α. WO2011057112A1, 2011; CAplus AN 2011:593981.
225. Gardner, J. H.; Shalwitz, R. Compositions and Methods for Treating Colitis. WO2011057121A1, 2011; CAplus AN 2011:585632.
226. Ghisalberti, C. Hexadentate Chelators in Inflammatory Bowel Disease. WO2010133907A1, 2010; CAplus AN 2010:1467953.
227. Taylor, R. Compositions Using Metal Ion Chelating Agents for Treatment of Intestinal Conditions. WO2006114630A1, 2006; CAplus AN 2006:1157424.
228. Kontoghiorghes, G. J. New orally active α-ketohydroxy pyridine chelators for the treatment of iron overload Birth Defects, Orig. Artic. Ser. 1988, 23, 97-103
229. Hewitt, S. D.; Hider, R. C.; Sarpong, P.; Morris, C. J.; Blake, D. R. Investigation of the anti-inflammatory properties of hydroxypyridinones Ann. Rheum. Dis. 1989, 48, 382-388
230. Aerpio. http://www.aerpio.com/about-aerpio.html (accessed August 13, 2012).
231. Allen, J. R.; Tegley, C. M.; Biswas, K.; Burli, R.; Muller, K. M.; Frohn, M. J.; Golden, J. E.; Mercede, S. J.; Neira, S. C.; Peterkin, T. A. N.; Hungate, R. W.; Kurzeja, R.; Yu, V.; Dao, J. Quinolone Based Compounds Exhibiting Prolyl Hydroxylase Inhibitory Activity, and Compositions, and Uses Thereof. WO2007070359A2, 2007; CAplus AN 2007:673402.
232. Allen, J. R.; Biswas, K.; Cao, G.-Q.; Golden, J. E.; Mercede, S.; Peterkin, T.; Reed, A.; Tegley, C. M. Preparation of Azaquinolone-Based Compounds Exhibiting Prolyl Hydroxylase Inhibitory Activity. WO2008076425A1, 2008; CAplus AN 2008:773803.
233. Allen, J. R.; Burli, R.; Frohn, M. J.; Hungate, R. W.; Neira, S. C.; Reed, A. B. Preparation of Thienopyridine- and Thiazolopyridine-Based Compounds Exhibiting Prolyl Hydroxylase Inhibitory Activity. WO2008137060A1, 2008; CAplus AN 2008:1360641.
234. Allen, J. R.; Biswas, K.; Burli, R.; Golden, J. E.; Mercede, S.; Tegley, C. M. Diazaquinolone Derivatives as HIF Prolyl Hydroxylase Inhibitors and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Diseases. WO2008137084A2, 2008; CAplus AN 2008:1363169.
235. Allen, J. R.; Burli, R.; Golden, J. E.; Muller, K. M.; Reed, A. B. Preparation of Indanone Derivatives as Prolyl Hydroxylase Inhibitors. WO2008130508A1, 2008; CAplus AN 2008:1300258.
236. Allen, J. R.; Biswas, K.; Bryan, M. C.; Burli, R.; Cao, G.-Q.; Frohn, M. J.; Golden, J. E.; Mercede, S.; Neira, S.; Peterkin, T.; Pickrell, A. J.; Reed, A.; Tegley, C. M.; Wang, X. Naphthalenone Compounds Exhibiting Prolyl Hydroxylase Inhibitory Activity, Compositions, Preparation and Uses Thereof. WO2008076427A2, 2008; CAplus AN 2008:769917.
237. Allen, J. R.; Burli, R.; Bryan, M. C.; Cao, G.-Q.; Neira, S. C.; Reed, A. B. Preparation of Quinolinones and Azaquinolinones as Prolyl Hydroxylase Inhibitors. WO2008130600A2, 2008; CAplus AN 2008:1299675.
238. Tegley, C. M.; Viswanadhan, V. N.; Biswas, K.; Frohn, M. J.; Peterkin, T. A. N.; Chang, C.; Buerli, R. W.; Dao, J. H.; Veith, H.; Rogers, N.; Yoder, S. C.; Biddlecome, G.; Tagari, P.; Allen, J. R.; Hungate, R. W. Discovery of novel hydroxy-thiazoles as HIF-α prolyl hydroxylase inhibitors: SAR, synthesis, and modeling evaluation Bioorg. Med. Chem. Lett. 2008, 18, 3925-3928
239. Frohn, M.; Viswanadhan, V.; Pickrell, A. J.; Golden, J. E.; Muller, K. M.; Buerli, R. W.; Biddlecome, G.; Yoder, S. C.; Rogers, N.; Dao, J. H.; Hungate, R.; Allen, J. R. Structure-guided design of substituted aza-benzimidazoles as potent hypoxia inducible factor-1α prolyl hydroxylase-2 inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 5023-5026
240. Poppe, L.; Tegley, C. M.; Li, V.; Lewis, J.; Zondlo, J.; Yang, E.; Kurzeja, R. J. M.; Syed, R. Different modes of inhibitor binding to prolyl hydroxylase by combined use of X-ray crystallography and NMR spectroscopy of paramagnetic complexes J. Am. Chem. Soc. 2009, 131, 16654-16655
241. Murray, J. K.; Balan, C.; Allgeier, A. M.; Kasparian, A.; Viswanadhan, V.; Wilde, C.; Allen, J. R.; Yoder, S. C.; Biddlecome, G.; Hungate, R. W.; Miranda, L. P. Dipeptidyl-quinolone derivatives inhibit hypoxia inducible factor-1α prolyl hydroxylases-1, -2, and -3 with altered selectivity J. Comb. Chem. 2010, 12, 676-686
242. Guiadeen, D.; Hale, J. J.; Kothandaraman, S. Preparation of Novel N -(4-Hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)carbonyl Substituted Amino Acid Derivatives as HIF Prolyl Hydroxylase Inhibitors for Treating Anemia. WO2008130527A1, 2008; CAplus AN 2008:1300268.
243. Colandrea, V. J.; Hale, J. J.; McCoy, J. G. Preparation of Tetrahydrofuropyridones as HIF Prolyl Hydroxylase Inhibitors. WO2009108496A1, 2009; CAplus AN 2009:1080467.
244. Debenham, J. S.; Hale, J. J.; Madsen-Duggan, C. B.; Walsh, T. F. Tetrahydrothieno Pyridines To Treat Anemia. WO2009108497A1, 2009; CAplus AN 2009:1080473.
245. Clements, M. J.; Colandrea, V. J.; Debenham, J. S.; Hale, J. J.; Madsen-Duggan, C. B.; Walsh, T. F. Tetrahydro-1 H -pyrrolo Fused Pyridones. WO2009108499A1, 2009; CAplus AN 2009:1081979.
246. Clements, M. J.; Debenham, J. S.; Hale, J. J.; Madsen-Duggan, C. B.; Walsh, T. F. Preparation of Substituted 4-Hydroxypyrimidine-5-carboxamides as HIF Prolyl Hydroxylase Inhibitors. WO2009117269A1, 2009; CAplus AN 2009:1168689.
247. Zhou, C.; Zou, W.; Hua, Y.; Dang, Q. Pyrimidine Derivatives as HIF Prolyl Hydroxylase Inhibitors and Their Preparation and Use for the Treatment of Anemia, WO2011130908A1, 2011; CAplus AN 2011:1375832.
248. Clements, M. J.; Debenham, J. S.; Hale, J. J.; Madsen-Duggan, C. Substituted 4-Hydroxypyrimidine-5-carboxamides and Use as Treatment for Anemia and Like Conditions. WO2011002624A1, 2011; CAplus AN 2011:19711.
249. Clements, M. J.; Debenham, J. S.; Hale, J. J.; Madsen-Duggan, C. Substituted 4-Hydroxypyrimidine-5-carboxamides and Use as Treatment for Anemia and Like Conditions. WO2011002623A1, 2011; CAplus AN 2011:19709.
250. Pierce, J. M.; Hale, J. J.; Miao, S.; Vachal, P. Preparation of Triazaspirodecanedione Derivatives for Use as HIF Prolyl Hydroxylase Inhibitors. WO2010147776A1, 2010; CAplus AN 2010:1600796.
251. Bakshi, R. K.; Dellureficio, J. P.; Dobbelaar, P. H.; Guo, L.; He, S.; Hong, Q.; Nargund, R. P.; Ye, Z. Acylated Spiropiperidine Derivatives as Melanocortin-4 Receptor Modulators and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Obesity, Nicotine Addiction, Alcoholism and Sexual Dysfunction. WO2007047496A2, 2007; CAplus AN 2007:461966.
252. Fletcher, J. M.; Hale, J. J.; Miao, S.; Vachal, P. Spiroindalone Derivatives as HIF Prolyl Hydroxylase Inhibitors and Their Preparation, Pharmaceutical Compositions and Use in the Treatment of Anemia. WO2008144266A1, 2008; CAplus AN 2008:1448488.
253. Fletcher, J. M.; Hale, J. J.; Miao, S.; Vachal, P. Spiroazaindoles Useful as HIF Prolyl Hydroxylase Inhibitors to Treat Anemia. WO2009137291A2, 2009; CAplus AN 2009:1398815.
254. Hocutt, F. M.; Leonard, B. E.; Peltier, H. M.; Phuong, V. K.; Rabinowitz, M. H.; Rosen, M. D.; Tarantino, K. T.; Venkatesan, H.; Zhao, L. X. Preparation of Benzimidazoles as Prolyl Hydroxylase Inhibitors. WO2009134750A1, 2009; CAplus AN 2009:1363853.
255. Barrett, T. D.; Palomino, H. L.; Brondstetter, T. I.; Kanelakis, K. C.; Wu, X.; Haug, P. V.; Yan, W.; Young, A.; Hua, H.; Hart, J. C.; Tran, D.-T.; Venkatesan, H.; Rosen, M. D.; Peltier, H. M.; Sepassi, K.; Rizzolio, M. C.; Bembenek, S. D.; Mirzadegan, T.; Rabinowitz, M. H.; Shankley, N. P. Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1 H -benzoimidazol-2-yl)-1 H -pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor Mol. Pharmacol. 2011, 79, 910-920
256. Bembenek, S. D.; Hocutt, F. M.; Leonard, B. E., Jr.; Rabinowitz, M. H.; Rosen, M. D.; Tarantino, K. T.; Venkatesan, H. Preparation of Quinazolinones as Prolyl Hydroxylase Inhibitors. US20100204226A1, 2010; CAplus AN 2010:1003346.
257. Rabinowitz, M. H.; Rosen, M. D.; Tarantino, K. T.; Venkatesan, H. 1-(4-Aminoquinazolin-2-yl)-1 H -pyrazole-4-carboxylic Acid Derivatives as Prolyl Hydroxylase Inhibitors and Their Preparation and Use for the Treatment of Diseases. WO2012021830A1, 2012; CAplus AN 2012:234808.
258. Flamme, I.; Ergueden, J.-K.; Oehme, F.; Thede, K.; Karig, G.; Kuhl, A.; Wild, H.; Schuhmacher, J.; Kolkhof, P.; Baerfacker, L.; Huetter, J. Preparation of 4-pyridin-3-yl-1,2-dihydro-3 H -pyrazol-3-ones as Cardiovascular Agents. WO2006114213A1, 2006; CAplus AN 2006:1147034.
259. Jeske, M.; Flamme, I.; Stoll, F.; Beck, H.; Akbaba, M. Preparation of Dihydropyrazolones as HIF Prolyl Hydroxylase Inhibitors. WO2009129945A1, 2009; CAplus AN 2009:1326992.
260. Jeske, M.; Flamme, I.; Stoll, F.; Oehme, F.; Akbaba, M. Preparation of Dihydrotriazolones as HIF Prolylhydroxylase Inhibitors. DE102007049157A1, 2009; CAplus AN 2009:453690.
261. Jeske, M.; Flamme, I.; Stoll, F.; Oehme, F. Preparation of Dihydropyrazolthiones as HIF Prolylhydroxylase Inhibitors. DE102007048447A1, 2009; CAplus AN 2009:452272.
262. Haerter, M.; Beck, H.; Ellinghaus, P.; Berhoerster, K.; Greschat, S.; Thierauch, K.-H.; Suessmeier, F. Heteroaryl Oxadiazoles and Related Derivatives, Their Preparation, Pharmaceutical Compositions, and Use in Therapy. WO2010054763A1, 2010; CAplus AN 2010:628949.
263. Boyer, S.; Haerter, M.; Wickens, P.; Patel, M.; Kumarasinghe, E. S.; Bhargava, A. K.; Thierauch, K.-H.; Beck, H.; Greschat, S.; Ellinghaus, P.; Paulus, P.; Hess-Stumpp, H. Heteroaryl-Substituted Pyrazole Derivatives Useful for Treating Hyperproliferative Disorders and Diseases Associated with Angiogenesis and Their Preparation. WO2008141731A2, 2008; CAplus AN 2008:1427536.
264. Cho, J. M.; Lee, T. G.; Ro, S. G.; Kim, J. H.; Jeon, Y. H.; Hyun, Y. L.; Heo, Y. S. Crystal Structure of Human Prolyl 4-Hydroxylase Complexed with Oxoglutarate, and Use for Screening of Drugs for Treatment of Angina Pectoris, KR2005083506A, 2005; CAplus AN 2006:949340.
265. Kim, S. N.; Hong, Y. R.; Shin, D.; Ro, S.; Cho, J. M.; Lee, S.; Chang, H. J. Preparation of Pyridine Derivatives for Treating HIF-Related Disorders. WO2009037570A2, 2009; CAplus AN 2009:364439.
266. Hong, Y. R.; Lee, M. J.; Kim, J. M.; Park, S.; Lee, W.; Choi, J.-R.; Ro, S.; Cho, J. M.; Masamune, H.; Elliott, G. T. Pyridine Derivatives for Treating HIF-Related Disorders. WO2011056725A1, 2011; CAplus AN 2011:593837.
267. Hong, Y. R.; Shin, D.; Ro, S.; Cho, J. M.; Kim, H. T.; Lee, J. H.; Kim, J. M.; Lee, W. S.; Choi, J.-R. Preparation of Phenol Derivatives as HIF Activity Modulators. WO2010018458A2, 2010; CAplus AN 2010:214042.
268. Japan Tobacco. http://www.jt.com/investors/results/pharmaceuticals/pdf/P. L.20120206-E.pdf (accessed August 13, 2012).
269. Mitani, I.; Ogoshi, Y.; Matsui, T.; Yokota, M.; Terashita, M.; Motoda, D.; Ueyama, K.; Abe, H.; Hotta, T.; Ito, T. Preparation of Triazolopyridine Compounds as Prolyl Hydroxylase (PHD) Inhibitors and Erythropoietin (EPO) Production Inducers. WO2011007856A1, 2011; CAplus AN 2011:80088.
270. Theriault, J. R.; Felts, A. S.; Bates, B. S.; Perez, J. R.; Palmer, M.; Gilbert, S. R.; Dawson, E. S.; Engers, J. L.; Lindsley, C. W.; Emmitte, K. A. Discovery of a new molecular probe ML228: an activator of the hypoxia inducible factor (HIF) pathway Bioorg. Med. Chem. Lett. 2012, 22, 76-81
271. Schilt, A. A.; Chriswell, C. D.; Fang, T. A. New chromogens of the ferroin type. VII. 3-Substituted-1,2,4-triazines, 3,5-disubstituted-1,2,4- triazolines, and triazoles, and 2,4- and 2,6-bis(triazinyl) and triazolinyl substituted pyridines Talanta 1974, 21, 831-836
272. Buckley, D. L.; Van, M. I.; Gareiss, P. C.; Tae, H. S.; Michel, J.; Noblin, D. J.; Jorgensen, W. L.; Ciulli, A.; Crews, C. M. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction J. Am. Chem. Soc. 2012, 134, 4465-4468
273. Minamishima, Y. A.; Kaelin, W. G., Jr. Reactivation of hepatic EPO synthesis in mice after PHD loss Science 2010, 329, 407
274. Astellas. http://www.astellas.com/en/corporate/news/pdf/080402-eg.pdf (accessed October 14, 2012).
275. Bernhardt, W. M.; Wiesener, M. S.; Scigalla, P.; Chou, J.; Schmieder, R. E.; Guenzler, V.; Eckardt, K.-U. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD J. Am. Soc. Nephrol. 2010, 21, 2151-2156
276. Günzler, V.; Muthukrishnan, E.; Neumayer, H. H.; Sacherer, K.; Schmidt, R.; Mitzner, A.; Wiecek, A.; Piecha, G.; Ignacy, W.; Scigalla, P. Hypoxia and Development, Physiology and Disease. Presented at the Keystone Symposia, 2006, Breckenridge CO, U.S.; A216.
277. Frohna, P. A.; Milwee, S.; Pinkett, J.; Lee, T.; Moore-Perry, K.; Chou, J.; Ellison, R. H. Abstracts of Papers, 40th Annual Meeting of the American Society of Nephrology, San Francisco, CA, November 2-5, 2007; American Society of Nephrology: Washington, DC, 2007; SU-PO806.
278. Besarab, A.; Hulter, H. N.; Klaus, S.; Lee, T. T.; Lilienfeld, D. E.; Neff, T.; Piper, B. A.; Provenzano, R.; Yu, K.-H. P. FG-4592, a novel oral HIF prolyl hydroxylase inhibitor, elevates hemoglobin in anemic stage 3/4 CKD patients J. Am. Soc. Nephrol. 2010, 21, 95A
279. Provenzano, R.; Tumlin, J.; Zabaneh, R.; Linde, P.; Chou, J.; Zhong, M.; Neff, T.; Yu, K.-H. P. Pharmacokinetics of Oral FG-4592 to treat anemia in hemodialysis (HD) patients (PTS) Am. J. Kidney Dis. 2011, 57, B80
280. FibroGen, Inc. http://www.fibrogen.com/press/release/pr-1304365050 (accessed November 6, 2012).
281. Besarab, A.; Belo, D.; Diamond, S.; Martin, E.; Sun, C.; Lee, T.; Saikali, K.; Franco, M.; Leong, R.; Neff, T.; Yu, K.-H. P. Evaluation of hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for hemoglobin correction and maintenance in nondialysis chronic kidney disease patients for 16 and 24 weeks Nephrol., Dial., Transplant. 2012, 27, ii133-ii145
282. FibroGen, Inc. http://www.fibrogen.com/press/release/pr-1338763700 (accessed October 12, 2012).
283. Bakris, G. L.; Yu, K.-H. P.; Leong, R.; Shi, W.; Lee, T.; Saikali, K.; Henry, E.; Neff, T. B. Abstracts of Papers, 27th Annual Scientific Meeting of the American Society of Hypertension, New York, NY, May 19-22, 2012; American Society of Hypertension: New York, NY, 2012; LB-OR-06.
284. Provenzano, P.; Besarab, A.; Dua, S. L.; Nguyen, P. V.; Wright, S. H.; Zeig, S.; Leong, R.; Chou, J.; Shi, W.; Saikali, K. G.; Yu, K.-H. P.; Neff, T. B. Abstracts of Papers, American Society of Nephrology Kidney Week, San Diego, CA, Oct 30-Nov 4, 2012; American Society of Nephrology: Washington, DC, 2012; Issue 23, p 428A.
285. GlaxoSmithKline. http://gsk-clinicalstudyregister.com/protocol-comp-list. jsp?compound=GSK1278863&studyType=All&phase=All&population= All&marketing=All&status=All&country=All (accessed October 20, 2012).
286. GlaxoSmithKline. http://www.clinicaltrials.gov/ct2/show/NCT00750256?term= phx111427&rank=1 (accessed October 20, 2012).
287. GlaxoSmithKline. http://download.gsk-clinicalstudyregister.com/files/ 50d2e8bc-ac8d-45b3-a7ac-628c6d17fee4 (accessed October 20, 2012).
288. GlaxoSmithKline. http://download.gsk-clinicalstudyregister.com/files/ 22712940-0ccd-454d-bc22-5a3926f16c16 (accessed October 22, 2012).
289. GlaxoSmithKline. http://download.gsk-clinicalstudyregister.com/files/ 34085017-2720-4b66-8748-862e1073e576 (accessed October 22, 2012).
290. GlaxoSmithKline. http://download.gsk-clinicalstudyregister.com/files/ db763bc6-6f57-448e-a6da-e773038d6ce1 (accessed October 22, 2012).
291. GlaxoSmithKline. http://download.gsk-clinicalstudyregister.com/files/ 66089135-d830-4570-8915-c0f9d84dba29 (accessed October 22, 2012).
292. GlaxoSmithKline. http://download.gsk-clinicalstudyregister.com/files/ e26ac3df-68b7-4e2e-bcd4-b0ef1b0f2bc0 (accessed October 22, 2012).
293. Bayer Healthcare. http://healthcare.bayer.de/scripts/pages/de/forschung- und-entwicklung/klinische-studien/datenbank-klinische-studien/ trialfinder-detail.php?trialid=15557&search=BAY-85-3934&product= &overall-status=&country=&phase=&condition=&results= 0&trials=0&btnSubmit=Search&num=10&show=1 (accessed November 11, 2012).
294. Bayer Healthcare. http://healthcare.bayer.de/scripts/pages/de/forschung- und-entwicklung/klinische-studien/datenbank-klinische-studien/ trialfinder-detail.php?trialid=14627&search=BAY-85-3934&product= &overall-status=&country=&phase=&condition=&results= 0&trials=0&btnSubmit=Search&num=10&show=1 (accessed November 11, 2012).
295. Bayer Healthcare. http://healthcare.bayer.de/scripts/pages/de/forschung- und-entwicklung/klinische-studien/datenbank-klinische-studien/ trialfinder-detail.php?trialid=14631&search=BAY-85-3934&product= &overall-status=&country=&phase=&condition=&results= 0&trials=0&btnSubmit=Search&num=10&show=1 (accessed November 11, 2012).
296. Bayer Healthcare. http://healthcare.bayer.de/scripts/pages/de/forschung- und-entwicklung/klinische-studien/datenbank-klinische-studien/ trialfinder-detail.php?trialid=16370&search=BAY-85-3934&product= &overall-status=&country=&phase=&condition=&results= 0&trials=0&btnSubmit=Search&num=10&show=1 (accessed November 11, 2012).
297. Akebia Therapeutics. http://www.akebia.com/news/AKB6548-Phase1.pdf (accessed October 17, 2012).
298. Akebia Therapeutics. http://www.akebia.com/news/AKB6548-Phase1a- Completion.pdf (accessed October 17, 2012).
299. Akebia Therapeutics. http://www.akebia.com/news/AKB6548-Phase2a- Initiation.pdf (accessed October 17, 2012).
300. Akebia Therapeutics. http://www.akebia.com/news/AKB6548-Phase2a-SD- Completion.pdf (accessed October 17, 2012).
301. Akebia Therapeutics. http://www.akebia.com/news/AKB6548-Phase-2a-Pilot- Study-Results.pdf (accessed October 17, 2012).
302. Akebia Therapeutics. http://www.akebia.com/news/AKB6548-Phase-2a-42-day. pdf (accessed October 17, 2012).
303. Akebia Therapeutics. http://www.akebia.com/news/AKB6548-Completes-Phase- 2-42-day.pdf (accessed October 17, 2012).
304. Bianchi, L.; Tacchini, L.; Cairo, G. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation Nucleic Acids Res. 1999, 27, 4223-4227
305. Warnecke, C.; Griethe, W.; Weidemann, A.; Jurgensen, J. S.; Willam, C.; Bachmann, S.; Ivashchenko, Y.; Wagner, I.; Frei, U.; Wiesener, M.; Eckardt, K.-U. Activation of the hypoxia-inducible factor pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors FASEB J. 2003, 17, 1186-1188
306. Mazzone, M.; Dettori, D.; Leite, d. O. R.; Loges, S.; Schmidt, T.; Jonckx, B.; Tian, Y.-M.; Lanahan, A. A.; Pollard, P.; Ruiz, d. A. C.; De, S. F.; Vinckier, S.; Aragones, J.; Debackere, K.; Luttun, A.; Wyns, S.; Jordan, B.; Pisacane, A.; Gallez, B.; Lampugnani, M. G.; Dejana, E.; Simons, M.; Ratcliffe, P.; Maxwell, P.; Carmeliet, P. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization Cell 2009, 136, 839-851
307. Okumura, C. Y. M.; Hollands, A.; Tran, D. N.; Olson, J.; Dahesh, S.; Koeckritz-Blickwede, M.; Thienphrapa, W.; Corle, C.; Jeung, S. N.; Kotsakis, A.; Shalwitz, R. A.; Johnson, R. S.; Nizet, V. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection J. Mol. Med. 2012, 90, 1079-1089.