Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia

Bibliography

• Worldwide prevalence of anaemia, 1993 – 2005, WHO Global Databaseon Anaemia. Available from: http://whqlibdoc.who.int/publications/2008/978 9241596657_eng.pdf
   Google Scholar
• Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006;107:1747-50
   PubMed Web of Science ®Google Scholar
• Perutz MF. Structure and mechanism of hemoglobin. Br Med Bull 1976;32:195-208
   PubMed Web of Science ®Google Scholar
• Brown R. Plasma erythropoietin in chronic uraemia. Br Med J 1965;2:1036-8
   Google Scholar
• Egrie JC, Strickland TW, Lane J, Characterization and biological effects of recombinant human erythropoietin. Immunobiology 1986;172:213-24
   PubMed Web of Science ®Google Scholar
• Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev 1992;72:449-89
   PubMed Web of Science ®Google Scholar
• Jacobs K, Shoemaker R, Rurensdorf R, Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 1985;313(6005):806
   Google Scholar
• Lin F-K, Lin P-H, Lai JK, Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 1985;82:7580-4
   PubMed Web of Science ®Google Scholar
• Eschbach JW, Kelly MR, Haley NR, Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 1989;321:158-63
   PubMed Web of Science ®Google Scholar
• Eschbach JW, Abdulhadi HM, Browne JK, Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III clinical trial. Ann Intern Med 1989;111:992-1000
   PubMed Web of Science ®Google Scholar
• Jelkmann W. Developments in the therapeutic use of erythropoiesis stimulating agents. Br J Haematol 2008;141:287-97
   PubMed Web of Science ®Google Scholar
• FibroGen, Inc. Avaialble from: http://www.fibrogen.com/anemial_market. [Accessed on 18 April 2010]
   Google Scholar
• Wish J, Schulman K, Law A, Healthcare expenditure and resource utilization in patients with anaemia and chronic kidney disease: a retrospective claims database analysis. Kidney Blood Press Res 2009;32:110-18
   PubMed Web of Science ®Google Scholar
• Semenza GL, Wang G. 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;12:5447-54
   PubMed Web of Science ®Google Scholar
• Fraisl P, Aragones J, Carmeliet P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov 2009;8:139-52
   PubMed Web of Science ®Google Scholar
• Semenza GL. Regulation of mammalian O2 hoeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999;15:551-78
   PubMed Web of Science ®Google Scholar
• Wang GL, Semenza GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993;268:21513-18
   PubMed Web of Science ®Google Scholar
• Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995;270:1230-7
   PubMed Web of Science ®Google Scholar
• Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 1997;11:72-82
   PubMed Web of Science ®Google Scholar
• Ema M, Taya S, Yokotani N, A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 1997;94:4273-8
   PubMed Web of Science ®Google Scholar
• Flamme I, Frohlich T, von Reutern M, HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1alpha and developmentally expressed in blood vessels. Mech Dev 1997;63:51-60
   PubMed Web of Science ®Google Scholar
• Gu Y-Z, Moran SM, Hogenesch JB, Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Expr 1998;7:205-13
   PubMed Web of Science ®Google Scholar
• Hoffman EC, Reyes H, Chu FF, Cloning of a factor required for activity of the Ah(dioxin) receptor. Science 1991;252:954-8
   PubMed Web of Science ®Google Scholar
• Li H, Ko HP, Whitlock JP. Induction of phosphoglycerate kinase 1 gene expression by hypoxia. Roles of Arnt and HIF 1alpha. J Biol Chem 1996;271:21262-7
   PubMed Web of Science ®Google Scholar
• Rankin EB, Biju MP, Liu Q, Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 2007;117:1068-77
   PubMed Web of Science ®Google Scholar
• Percy MJ, Furlow PW, Lucas GS, A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 2008;358:162-8
   PubMed Web of Science ®Google Scholar
• Martini M, Teofili L, Cenci T, A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis. Haematologica 2008;93:1068-71
   PubMed Web of Science ®Google Scholar
• Furlow PW, Percy MJ, Sutherland S, Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J Biol Chem 2009;284:9050-8
   PubMed Web of Science ®Google Scholar
• Gruber M, Hu C-J, Johnson RS, Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci USA 2007;104:2301-6
   PubMed Web of Science ®Google Scholar
• Fong G-H. Regulation of angiogenesis by oxygen sensing mechanisms. J Mol Med 2009;87:549-60
   Google Scholar
• Huang LE, Arany Z, Livingston DM, Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 1996;271:32253-9
   PubMed Web of Science ®Google Scholar
• Huang LE, Gu J, Schau M, Regulation of hypoxia-inducible factor 1a is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1998;95:7987-92
   PubMed Web of Science ®Google Scholar
• Semenza GL, Jiang B-H, Leung SW, 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;271:32529-37
   PubMed Web of Science ®Google Scholar
• Wang GL, Jiang BH, Rue EA, Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510-14
   PubMed Web of Science ®Google Scholar
• Massari ME, Murre C. Helix-loop helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 2000;20:429-40
   PubMed Web of Science ®Google Scholar
• Moglich A, Ayers RA, Moffat K. Structure and signaling mechanism of Per-ARNT-Sim domains. Structure 2009;17:1282-94
   PubMed Web of Science ®Google Scholar
• Cockman ME, Masson N, Mole DR, Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000;275:25733-41
   PubMed Web of Science ®Google Scholar
• Semenza GL, Nejfelt MK, Chi SM, Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci USA 1991;88:5680-4
   PubMed Web of Science ®Google Scholar
• Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993;90:4304-8
   PubMed Web of Science ®Google Scholar
• Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors in iron metabolism. Cell Cycle 2008;7:28-32
   PubMed Web of Science ®Google Scholar
• Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007;117:1926-32
   PubMed Web of Science ®Google Scholar
• Hirsila M, Koivunen P, Gunzler V. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem 2003;278:30772-80
   PubMed Web of Science ®Google Scholar
• Ehrismann D, Flashman E, Genn DN, Studies on the activity of the hypoxia-inducible-factor hydroxylases using an oxygen consumption assay. Biochem J 2007;401:227-34
   PubMed Web of Science ®Google Scholar
• Ivan M, Kondo K, Yang H. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001;292:464-8
   PubMed Web of Science ®Google Scholar
• Jaakkola P, Mole DR, Tian Y-M. Targeting of HIF-alpha to the von Hippel-Lindau Ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468-72
   PubMed Web of Science ®Google Scholar
• Yu F, White SB, Zhao Q, HIF-1a binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 2001;98:9630-5
   PubMed Web of Science ®Google Scholar
• Min JH, Yang H, Ivan M, Structure of an HIF-1alpha—pVHL complex: hydroxyproline recognition in signaling. Science 2002;296:1886-9
   PubMed Web of Science ®Google Scholar
• Maxwell PH, Wiesener MS, Chang G-W, The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271-6
   PubMed Web of Science ®Google Scholar
• Ohh M, Park CW, Ivan M, Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000;2:423-7
   PubMed Web of Science ®Google Scholar
• Kamura T, Sato S, Iwai K, Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 2000;97:10430-5
   PubMed Web of Science ®Google Scholar
• Paltoglou S, Roberts BJ. HIF-1alpha and EPAS ubiquitination mediated by the VHL tumor suppressor involves flexibility in the ubiquitination mechanism, similar to other RING E3 ligases. Oncogene 2007;26:604-9
   PubMed Web of Science ®Google Scholar
• Min J-H, Yang H, Ivan M, Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science 2002;296:1886-9
   PubMed Web of Science ®Google Scholar
• Hon W-C, Wilson MI, Harlos K, Structural basis for the recognition of hydroxy-proline in HIF1alpha by pVHL. Nature 2002;417:975-8
   PubMed Web of Science ®Google Scholar
• Berchner-Pfannschmidt U, Tug S, Trinidad B, Nuclear oxygen sensing: induction of endogenous prolyl-hydroxylase 2 activity by hypoxia and nitric oxide. J Biol Chem 2008;283:31745-53
   PubMed Web of Science ®Google Scholar
• Lando D, Peet DJ, Whelan DA, Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 2002;295:858-61
   PubMed Web of Science ®Google Scholar
• Wang Q, VanDusen WJ, Petroski CJ, Bovine liver aspartyl beta-hydroxylase. J Biol Chem 1991;266:14004-10
   Google Scholar
• Dames SA, Martinez-Yamout M, De Guzman RN, Structural basis for HIF1alpha/CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci USA 2002;99:5271-6
   PubMed Web of Science ®Google Scholar
• Freedman SJ, Sun Z-YJ, Poy F, Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1alpha. Proc Natl Acad Sci USA 2002;99:5367-72
   PubMed Web of Science ®Google Scholar
• Koivunen P, Hirsila M, Gunzler V, Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem 2004;279:9899-904
   PubMed Web of Science ®Google Scholar
• Schfield CJ, Ratcliffe PJ. Signalling hypoxia by HIF hydroxylases. Biochem Biophys Res Commun 2005;338:617-26
   Google Scholar
• Cioffi CL, Liu XQ, Kosinski PA, Differential regulation of HIF-1alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells. Biochem Biophys Res Commun 2003;303:947-53
   PubMed Web of Science ®Google Scholar
• Oehme F, Ellinghaus P, Kolkhof P, Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun 2002;296:343-9
   PubMed Web of Science ®Google Scholar
• Koivunen P, Tiainen P, Hyvarinen J, An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J Biol Chem 2007;282:30544-52
   PubMed Web of Science ®Google Scholar
• Metzen E, Berchner-Pfannschmidt U, Stengel P. Intracellular localization of human HIF-1alpha hydroxylases: implications for oxygen sensing. J Cell Sci 2003;116:1319-26
   PubMed Web of Science ®Google Scholar
• Berra E, Benizri E, Ginouves, HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J 2003;22:4082-90
   PubMed Web of Science ®Google Scholar
• Berchner-Pfannschmidt U, Tug S, Trinidad B, Nuclear oxygen sensing: induction of endogenous prolyl-hydroxylase 2 activity by hypoxia and nitric oxide. J Biol Chem 2008;283:31745-53
   PubMed Web of Science ®Google Scholar
• Stiehl DP, Wirthner R, Koditz J, Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels. J Biol Chem 2006;281:23482-91
   PubMed Web of Science ®Google Scholar
• Clifton IJ, McDonough MA, Ehrismann D, Structural studies on 2-oxoglutarate oxygenases and related double-stranded b-helix fold proteins. J Inorg Biochem 2006;100:644-69
   PubMed Web of Science ®Google Scholar
• Ozer A, Bruick RK. Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one? Nat Chem Biol 2007;3:144-53
   PubMed Web of Science ®Google Scholar
• McDonough MA, Li V, Flashman E, Cellular oxygen sensing: crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci USA 2006;103:9814-19
   PubMed Web of Science ®Google Scholar
• Chowdhury R, McDonough MA, Mecinovic J, Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. Structure 2009;17:981-9
   PubMed Web of Science ®Google Scholar
• Myllyharju J. HIF prolyl 4-hydroxylases and their potential as drug targets. Curr Pharm Des 2009;15:3878-85
   PubMed Web of Science ®Google Scholar
• Bruegge K, Jelkmann W, Metzen E. Hydroxylation of hypoxia-inducible transcription factors and chemical compounds targeting the HIF-alpha hydroxylases. Curr Med Chem 2007;14:1853-62
   PubMed Web of Science ®Google Scholar
• Roy A, Volgin DV, Baby SM, Activation of HIF-1alpha mRNA by hypoxia and iron chelator in isolated rat carotid body. Neurosci Lett 2004;363:229-32
   Google Scholar
• Linden T, Katschinski DM, Eckhardt K, The antimycotic ciclopirox olamine induces HIF-1alpha stability, VEGF expression, and angiogenesis. FASEB J 2003;17:761-3
   PubMed Web of Science ®Google Scholar
• Hirsila M, Koivunen P, Xu L, Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J 2005;19:1308-10
   PubMed Web of Science ®Google Scholar
• Goldberg MA, Dunning SP, Bunn HF. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science 1988;242:1412-15
   PubMed Web of Science ®Google Scholar
• Salnikow K, Donald SP, Bruick RK, Depletion of intracellular ascorbate by the carcinogenic metals nickel and cobalt results in the induction of hypoxic stress. J Biol Chem 2004;279:40337-44
   PubMed Web of Science ®Google Scholar
• Kivirikko KI, Myllyla R. Posttranslational enzymes in the biosynthesis of collagen: intracellular enzymes. Methods Enzymol 1982;82:245-304
   PubMed Web of Science ®Google Scholar
• Kanelakis KC, Palomino HL, Li L, Characterization of a robust enzymatic assay for inhibitors of 2-oxoglutarate-dependent hydroxylases. J Biomol Screen 2009;14:627-35
   PubMed Web of Science ®Google Scholar
• FibroGen, Inc. HIF prolyl hydroxylase activity assay. WO2005118836; 2007
   Google Scholar
• Li D, Hirsila M, Koivunen P, Many amino acid substitutions in a hypoxia-inducible transcription factor (HIF)-1alpha-like peptide cause only minor changes in its hydroxylation by the HIF prolyl 4-hydroxylases. J Biol Chem 2004;279:55051-9
   PubMedGoogle Scholar
• Dao JH, Kurzeja RJM, Morachis JM, 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;384:213-23
   PubMed Web of Science ®Google Scholar
• Tegley CM, Viswanadhan VN, Biswas K, Discovery of novel hydroxyl-thiazoles as HIF-alpha prolyl hydroxylase inhibitors: SAR, synthesis, and modeling evaluation. Bioorg Med Chem Lett 2008;18:3925-8
   Google Scholar
• Frohn M, Viswanadhan V, Pickrell AJ, Structure-guided design of substituted aza-benzimidazoles as potent hypoxia inducible factor-1alpha prolyl hydroxylase-2 inhibitors. Bioorg Med Chem Lett 2008;18:5023-6
   PubMed Web of Science ®Google Scholar
• Oehme F, Jonghaus W, Narouz-Ott L, A nonradioactive 96-well plate assay for the detection of hypoxia-inducible factor prolyl hydroxylase activity. Anal Biochem 2004;330:74-80
   PubMed Web of Science ®Google Scholar
• FibroGen, Inc. Stabilization of hypoxia inducible factor (HIF) alpha. WO2003049686; 2003
   Google Scholar
• FibroGen, Inc. Methods of increasing endogenous EPO. WO2003053997; 2003
   Google Scholar
• FibroGen, Inc. Treatment method for anemia. US20060276477; 2006
   Google Scholar
• FibroGen, Inc. Compounds and methods for treatment of chemotherapy-induced anemia. US20070292433; 2007
   Google Scholar
• FibroGen, Inc. HIF hydroxylase inhibitors for treatment of cancer-related anemia. US20070293575; 2007
   Google Scholar
• FibroGen, Inc. Use of HIF alpha stabilizers for enhancing erythropoiesis. WO2004108121; 2004
   Google Scholar
• FibroGen, Inc. Cytoprotection through the use of HIF hydroxylase inhibitors. US20060251638; 2006
   Google Scholar
• FibroGen, Inc. Fat regulation. WO2004052285; 2004
   Google Scholar
• FibroGen, Inc. Inhibitors of 2-oxoglutarate dioxygenase as gamma globin inducers. WO2005011696; 2005
   Google Scholar
• FibroGen, Inc. Tissue remodeling and vascularization. WO2005034929; 2005
   Google Scholar
• FibroGen, Inc. Treatment of diabetes. WO2004052284; 2004
   Google Scholar
• FibroGen, Inc. Methods of identifying therapeutic targets for the treatment of vulvovaginal atrophy. WO2006099610; 2006
   Google Scholar
• FibroGen, Inc. Compounds and methods for treatment of stroke. WO2007097929; 2007
   Google Scholar
• FibroGen, Inc. Methods for increasing endothelial progenitor cells. WO2009075824; 2009
   Google Scholar
• FibroGen, Inc. Methods for increasing white blood cells. WO2009075826; 2009
   Google Scholar
• FibroGen, Inc. Compounds and methods for treatment of cancer. WO2006138511; 2006
   Google Scholar
• FibroGen, Inc. Methods for reducing blood pressure. WO2009058403; 2009
   Google Scholar
• FibroGen, Inc. Phenanthroline derivatives. WO9921860; 1999
   Google Scholar
• Ivan M, Haberberger T, Gervasi DC, Bichemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci USA 2002;99:13459-64
   PubMed Web of Science ®Google Scholar
• FibroGen, Inc. Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin. WO2004108681; 2004
   Google Scholar
• Thevis M, Kohler M, Schlorer N, Gas phase reaction of substituted isoquinolines to carboxylic acids in ion trap and triple quadrupole mass spectrometers after electrospray ionization and collision-induced dissociation. J Am Soc Mass Spectrom 2008;19:151-8
   PubMed Web of Science ®Google Scholar
• Warshakoon NC, Wu S, Boyer A, Design and synthesis of a series of novel pyrazolopyridines as HIF 1-alpha prolyl hydroxylase inhibitors. Bioorg Med Chem Lett 2006;16:5687-90
   PubMed Web of Science ®Google Scholar
• Stubbs CJ, Loenarz C, Mecinovic J, Application of a proteolysis/mass spectrometry method for investigating the effects of inhibitors on hydroxylase structure. J Med Chem 2009;52:2799-805
   Google Scholar
• FibroGen, Inc. Novel thienopyridine compounds, and methods of use thereof. WO2006094292; 2006
   Google Scholar
• FibroGen, Inc. Cyanoisoquinoline compounds and methods of use thereof. WO2007090068; 2007
   Google Scholar
• FibroGen, Inc. Preparation of pyrrolopyridines and thiazolopyridines, particularly N-[(4-hydroxy-1H-pyrrolo[2,3-c]pyridin-5-yl)carbonyl]glycine and N-[(7-hydroxythiazolo[4,5-c]pyridine-6-yl)carbonyl]glycine derivatives, as hypoxia inducible factor hydroxylase modulators. WO2007115315; 2007
   Google Scholar
• FibroGen, Inc. Isoxazolopyridine derivatives for use in the treatment of HIF-mediated conditions. WO2009073669; 2009
   Google Scholar
• FibroGen, Inc. Isothiazole-pyridine derivatives as modulators of HIF (hypoxia inducible factor) activity. WO2009089547; 2009
   Google Scholar
• FibroGen, Inc. Chromene derivatives and use thereof as HIF hydroxylase activity inhibitors. WO2009100250; 2009
   Google Scholar
• FibroGen, Inc. Thiochromene derivatives as HIF hydroxylase inhibitors. WO2010056767; 2010
   Google Scholar
• FibroGen, Inc. Pyrrolo[1,2-b]pyridazine derivatives and their use as HIF modulators. WO2010022240; 2010
   Google Scholar
• GlaxoSmithKline. Anti-infectives. WO2004052313; 2004
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase antagonists. WO2007038571; 2007
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2007103905; 2007
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2007136990; 2007
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009039323; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009039321; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009039322; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2010022307; 2010
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009070644; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009073497; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009134850; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009134847; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2007150011; 2007
   Google Scholar
• GlaxoSmithKline. N-Substituted glycine derivatives: prolyl hydroxylase inhibitors. US20080171756; 2008
   Google Scholar
• GlaxoSmithKline. N-Substituted glycine derivatives: hydroxylase inhibitors. WO2008089052; 2008
   Google Scholar
• GlaxoSmithKline. N-Glycinyl pyridinedicarboxamide derivatives as HIF prolyl hydroxylase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of anemia. WO2009158315; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2010025087; 2010
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009049112; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2009086044; 2009
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2010022308; 2010
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2010059549; 2010
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2010059552; 2010
   Google Scholar
• GlaxoSmithKline. Prolyl hydroxylase inhibitors. WO2010059555; 2010
   Google Scholar
• Amgen. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof. WO2007070359; 2007
   Google Scholar
• Amgen. Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof. WO2008076425; 2008
   Google Scholar
• Stubbs CJ, Loenarz C, Mecinovic J, Application of a proteolysis/mass spectrometry method for investigating the effects of inhibitors on hydroxylase structure. J Med Chem 2009;52:2799-805
   Google Scholar
• Amgen. Diazaquinolones that inhibit prolyl hydroxylase activity. WO2008137084; 2008
   Google Scholar
• Amgen. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof. WO2008076427; 2008
   Google Scholar
• Amgen. Indanone derivatives that inhibit prolyl hydroxylase. WO2008130508; 2008
   Google Scholar
• Amgen. Quinolones and azaquinolones that inhibit prolyl hydroxylase. WO2008130600; 2008
   Google Scholar
• Amgen. Thienopyridine and thiazolopyridine derivatives that inhibit prolyl hydroxylase activity. WO2008137060; 2008
   Google Scholar
• Bayer. 4-(Pyridin-3-yl)-2-(pyridine-2-yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-prolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases. WO2006114213; 2006
   Google Scholar
• Bayer. Substituted dipyridyl-dihydropyrazolones and use thereof. WO2008067874; 2008
   Google Scholar
• Bayer. Substituted heterocyclic compounds and their use. DE102007044032; 2007
   Google Scholar
• Bayer. Substituted dihydropyrazolones and use thereof as HIF-prolyl-4-hydroxylase inhibitors. WO2008049538; 2008
   Google Scholar
• Bayer. Substituted dihydropyrazolthiones and their use. DE102007048447; 2007
   Google Scholar
• Bayer. Substituted dihydrotriazolones and their use. DE102007049157; 2007
   Google Scholar
• Bayer. Substituted dihydropyrazolones for treating cardiovascular and haematological diseases. WO2008067871; 2008
   Google Scholar
• Bayer. Substituted dihydropyrazolones and their use. US20090269420; 2009
   Google Scholar
• Merck. Novel 1,8-naphthyridine compounds. WO2008130527; 2008
   Google Scholar
• Merck. Tetrahydrofuropyridines. WO2009108496; 2009
   Google Scholar
• Merck. Tetrahydrothienopyridines. WO2009108497; 2009
   Google Scholar
• Merck. Tetrahydro-1H-pyrrolo fused pyridones. WO2009108499; 2009
   Google Scholar
• Merck. Spiroindalones. WO2008144266; 2008
   Google Scholar
• Merck. Spiroazaindoles. WO2009137291; 2009
   Google Scholar
• Merck. Substituted 4-hydroxypyrimidine-5-carboxamides. WO2009117269; 2009
   Google Scholar
• Janssen. Benzoimidazoles as prolyl hydroxylase inhibitors. WO2009134750; 2009
   Google Scholar
• Benzoimidazoles glycinamides as prolyl hydroxylase inhibitors. WO2009134754; 2009
   Google Scholar
• Procter & Gamble. Three dimensional coordinates of hypoxia inducible factor 1 alpha (HIF-1alpha)-prolyl hydroxylase (EGLN1) and uses thereof. US20080124740; 2008
   Google Scholar
• Warshakoon NC, Wu S, Boyer A, Structure-based design, synthesis, and SAR evaluation of a new series of 8-hydroxyquinolines as HIF-1alpha prolyl hydrolase inhibitors. Bioorg Med Chem Lett 2006;16:5517-22
   PubMed Web of Science ®Google Scholar
• Warshakoon NC, Wu S, Boyer A, Design and synthesis of substituted pyridine derivatives as HIF-1alpha prolyl hydrolase inhibitors. Bioorg Med Chem Lett 2006;16:5616-20
   Google Scholar
• Warshakoon NC, Wu S, Boyer A, A novel series of imidazo[1,2-a]pyridine derivatives as HIF-1alpha prolyl hydrolase inhibitors. Bioorg Med Chem Lett 2006;16:5598-601
   PubMed Web of Science ®Google Scholar
• Procter & Gamble. Prolyl hydroxylase inhibitors and methods of use. US20070299086; 2007
   Google Scholar
• CrystalGenomics. Pyridine derivatives and methods of use thereof. WO2009037570; 2009
   Google Scholar
• CrystalGenomics. Phenol derivatives and methods of use thereof. WO2010018458; 2010
   Google Scholar
• Kowa. Prophylactic and/or therapeutic agent for anemia comprising 2-phenylquinoline-4-carboxylic acid derivative as active ingredient. WO2009016812; 2009
   Google Scholar
• Nagel S, Talbot NP, Mecinovic J, Therapeutic manipulation of the HIF hydroxylases. Antioxid Redox Signal 2010;12:481-501
   PubMed Web of Science ®Google Scholar
• Urquilla P, Fong A, Oksanen S, Upregulation of endogenous erythropoietin (EPO) in healthy subjects by inhibition of hypoxia inducible factor (HIF) prolyl hydroxylase. American Society of Hematology 2004 Annual Meeting. Blood 2004;104: abstract 174
   Google Scholar
• Kim Y, Lin Q, Glazer PM, Hypoxic tumor microenvironment and cancer cell differentiation. Curr Mol Med 2009;9:425-34
   Google Scholar
• Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer. J Cell Biochem 2009;107:1053-62
   PubMed Web of Science ®Google Scholar
• Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721-32
   PubMed Web of Science ®Google Scholar
• Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med 2002;8:S62-7
   PubMed Web of Science ®Google Scholar
• Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 2003;9:677-84
   PubMed Web of Science ®Google Scholar
• Henke M, Laszig R, Rube C, Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomized, double-blind, placebo-controlled trial. Lancet 2003;362:1255-60
   PubMed Web of Science ®Google Scholar
• Leyland-Jones B, Semiglazov V, Pawlicki M, Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005;23:5960-72
   PubMed Web of Science ®Google Scholar
• Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol 2004;22:4991-5004
   PubMed Web of Science ®Google Scholar
• Ivan M, Kaelin WG. The von Hippel-Lindau tumor suppressor protein. Curr Opin Genet Dev 2001;11:27-34
   PubMed Web of Science ®Google Scholar
• Ladroue C, Carcenac R, Leporrier M, PHD2 mutation and congenital erythrocytosis with paragandlioma. N Engl J Med 2008;259:2685-92
   Google Scholar
• Amsel J, Waterbor JW, Oler J, Relationship of site-specific cancer mortality rates to altitude. Carcinogenesis 1982;3:461-5
   PubMed Web of Science ®Google Scholar
• Weinberg CR, Brown KG, Hoel DG. Altitude, radiation, and mortality from cancer and heart disease. Radiat Res 1987;112:381-90
   Google Scholar
• Thurston G, Suri C, Smith K, Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999;286:2511-14
   PubMed Web of Science ®Google Scholar
• Elson DA, Thurston G, Huang LE, Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha. Genes Dev 2001;15:2520-32
   PubMed Web of Science ®Google Scholar
• Mazzone M, Dettori D, de Oliveira RL, Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 2009;136:839-51
   PubMed Web of Science ®Google Scholar
• Pastore Y, Jedlickova K, Guan Y, Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Am J Hum Genet 2003;73:412-19
   PubMed Web of Science ®Google Scholar
• Ang SO, Chen H, Kirota K, Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 2002;32:614-21
   PubMed Web of Science ®Google Scholar
• Gordeuk VR, Sergueeva AI, Miasnikova GY, Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood 2004;103:3924-32
   PubMed Web of Science ®Google Scholar
• Ribatti D. Erythropietin and tumor angiogenesis. Stem Cells Dev 2010;19:1-4
   Google Scholar
• Percy MJ, Zhao Q, Flores A, A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci USA 2006;103:654-9
   PubMed Web of Science ®Google Scholar
• Percy MJ, Furlow PW, Beer PA, A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood 2007;110:2193-6
   PubMed Web of Science ®Google Scholar
• Al-Sheikh M, Moradkhani K, Lopez M, Disturbance in the HIF-1alpha pathway associated with erythrocytosis: further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. Blood Cells Mol Dis 2008;40:160-5
   PubMed Web of Science ®Google Scholar
• Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia inducible factor 1 DNA binding activity: implications for models of hypoxia signal transduction. Blood 1993;82:3610-15
   PubMed Web of Science ®Google Scholar
• Novartis Pharmaceuticals Corporation. Available from: http://www.pharma.us.novartis.com/product/pi/pdf/exjade.pdf [Accessed 12 April 2010]
   Google Scholar
• Lopez-Lazaro M. Role of oxygen in cancer: looking beyond hypoxia. Anticancer Agents Med Chem 2009;9:517-25
   Google Scholar
• Spivak J. Daily aspirin – only half the answer. N Engl J Med 2004;350:99-101
   PubMedGoogle Scholar
• Sergeyeva A, Gordeuk VR, Tokarev YN, Congenital polycythemia in Chuvashia. Blood 1997;89:2148-54
   PubMed Web of Science ®Google Scholar
• Unger EF, Thompson AM, Blank MJ, Erythropoiesis-stimulating agents – time for a reevaluation. N Engl J Med 2010;362:189
   PubMed Web of Science ®Google Scholar
• Lee FS. Genetic causes of erythrocytosis and the oxygen-sensing pathway. Blood Rev 2008;22:321-32
   Google Scholar
• Urquilla P. Up-regulation of endogenous EPO in healthy subjects by inhibition of HIF-PH. J Am Soc Nephrol 2004;15:546A
   Google Scholar
• Gunzler V, Muthukrishnan E, Neumayer HH, FG-2216 increases hemoglobin concentration in anemic patients with chronic kidney disease. J Am Soc Nephrol 2005;16:758A
   Google Scholar
• Yildiz P. Molecular mechanisms of pulmonary hypertension. Clin Chim Acta 2009;403:9-16
   PubMed Web of Science ®Google Scholar
• Hackett PH, Roach RC. High-altitude illness. N Engl J Med 2001;345:107-14
   PubMed Web of Science ®Google Scholar
• Maggiorini M, Leon-Velarde F. High-altitude pulmonary hypertension: a pathophysiological entity to different diseases. Eur Respir J 2003;22:1019-25
   PubMed Web of Science ®Google Scholar
• Bushuev VI, Miasnikova GY, Sergueeva AI, Endothelin-1, vascular endothelial growth factor and systolic pulmonary artery pressure in patients with Chuvash polycythemia. Haematologica 2006;91:744-9
   Google Scholar
• Smith TG, Brooks JT, Balanos GM, Mutation of von Hippel-Lindau tumor suppressor and human cardiopulmonary physiology. PLoS Med 2006;3:1178-86
   Web of Science ®Google Scholar
• Allegra A, Giacobbe MS, Corvaia E, Possible role of erythropoietin in the pathogenesis of chronic corpulmonale. Nephrol Dial Transplant 2005;20:2866-7
   PubMed Web of Science ®Google Scholar
• Beumi M, Senatore M, Gallo GC, Pulmonary hypertension and erythropoietin. Kidney Blood Press Res 2007;30:248-52
   Google Scholar
• Ali O, Wharton J, Gibbs JSR, Emerging therapies for pulmonary arterial hypertension. Expert Opin Investig Drugs 2007;16:803-18
   PubMed Web of Science ®Google Scholar
• Balanos GM, Dorrington KL, Robbins PA. Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1. J Appl Physiol 2002;92:2501-7
   Google Scholar
• Smith TG, Balanos GM, Croft QP, The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol 2008;586:5999-6005
   PubMed Web of Science ®Google Scholar
• Yu AY, Shimoda LA, Iyer NV, Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J Clin Invest 1999;103:691-6
   PubMed Web of Science ®Google Scholar
• Brusselmans K, Compernolle V, Tjwa M, Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest 2003;111:1519-27
   PubMed Web of Science ®Google Scholar
• Hickey MM, Lam JC, Bezman NA, Von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythrocytosis. J Clin Invest 2007;117:3879-89
   PubMed Web of Science ®Google Scholar
• Hickey MM, Richardson T, Wang T, The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest 2010;120:827-39
   PubMed Web of Science ®Google Scholar
• Pappalardi MB, Martin JD, Jiang Y, Biochemical characterization of human prolyl hydroxylase domain protein 2 variants associated with erythrocytosis. Biochemistry 2008;47:11165
   PubMed Web of Science ®Google Scholar
• Cummins EP, Berra E, Comeford KM, Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 2006;103:18154-9
   PubMed Web of Science ®Google Scholar
• Wenger RH, Camenisch G, Stiehl DP, HIF prolyl-4-hydroxylase interacting proteins: consequences for drug targeting. Curr Pharm Des 2009;15:3886-94
   PubMed Web of Science ®Google Scholar
• Loenarz C, Schofield CJ. Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 2008;4:152-6
   PubMed Web of Science ®Google Scholar