Patent
Prolyl hydroxylase inhibitors
| العنوان: | Prolyl hydroxylase inhibitors |
|---|---|
| Patent Number: | 8,536,181 |
| تاريخ النشر: | September 17, 2013 |
| Appl. No: | 12/940891 |
| Application Filed: | November 05, 2010 |
| مستخلص: | Disclosed herein are prolyl hydroxylase inhibitors that can stabilize hypoxia inducible factor-1 alpha (HIF-1α), as well as hypoxia inducible factor-2 (HIF-2). Also disclosed herein are pharmaceutical compositions comprising one or more of the disclosed compounds. Yet further disclosed are methods for stimulating the cellular immune response in a mammal such as increasing phagocytosis, for example, prolonging the life of phagocytes, inter alia, kerotyiocytes, neutrophils. As such the disclosed compounds provide methods for treating diseases that relate to the body's immune response. |
| Inventors: | Gardner, Joseph H. (Cincinnati, OH, US); Shalwitz, Robert (Bexley, OH, US) |
| Assignees: | Aerpio Therapeutics Inc. (Cincinnati, OH, US) |
| Claim: | 1. A compound having the formula: [chemical expression included] wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine; R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl; or a pharmaceutically acceptable salt thereof. |
| Claim: | 2. The compound according to claim 1 , wherein R 4 is methyl. |
| Claim: | 3. The compound according to claim 1 , wherein R 4 is ethyl. |
| Claim: | 4. The compound according to claim 1 , wherein R 4 is tert-butyl. |
| Claim: | 5. The compound according to claim 1 , wherein Z is 4-chlorophenyl. |
| Claim: | 6. The compound according to claim 1 , wherein Z is chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl. |
| Claim: | 7. The compound according to claim 1 , wherein Z is chosen from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl. |
| Claim: | 8. The compound tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate. |
| Claim: | 9. A compound chosen from: Methyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(4-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; and tert-Butyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate. |
| Claim: | 10. A compound according to claim 1 , wherein the compound is a pharmaceutically acceptable salt of an anion chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, hydrogensulfonate, p-toluenesulfonate, methanesulfonate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, glycolate, or citrate. |
| Claim: | 11. A composition comprising: a) one or more compounds having the formula: [chemical expression included] wherein Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine; R 4 is C 1 -C 4 linear alkyl or C 3 -C 4 branched alkyl; or a pharmaceutically acceptable salt thereof; and b) one or more pharmaceutically acceptable excipients. |
| Claim: | 12. The composition according to claim 11 , wherein R 4 is methyl. |
| Claim: | 13. The composition according to claim 11 , wherein R 4 is ethyl. |
| Claim: | 14. The composition according to claim 11 , wherein R 4 is tert-butyl. |
| Claim: | 15. The composition according to claim 11 , wherein Z is 4-chlorophenyl. |
| Claim: | 16. The composition according to claim 11 , wherein Z is chosen from 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl. |
| Claim: | 17. The composition according to claim 11 , wherein Z is chosen from 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and 2,6-dichlorophenyl. |
| Claim: | 18. The composition according to claim 11 , comprising tert-butyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl]methyl}piperazine-1-carboxylate. |
| Claim: | 19. The composition according to claim 11 , comprising one or more compounds chosen from: Methyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(2-chlorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(4-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(2-fluorobenzyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(4-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(2-chlorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Methyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; Ethyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(4-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; tert-Butyl 4-{[1-(3-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate; and tert-Butyl 4-{[1-(2-fluorophenylsulfonyl)-3-hydroxy-2-oxo-1,2-dihydropyridin-4-yl ]methyl}piperazine-1-carboxylate. |
| Claim: | 20. The composition according to claim 11 , wherein the compound is a pharmaceutically acceptable salt of an anion chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, hydrogensulfonate, p-toluenesulfonate, methanesulfonate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, glycolate, or citrate. |
| Current U.S. Class: | 51425/312 |
| Patent References Cited: | 3853900 December 1974 Shone et al. 3894920 July 1975 Kondo et al. 5358949 October 1994 Tabusa et al. 5397799 March 1995 Kress et al. 5407948 April 1995 Fey et al. 5620995 April 1997 Weidmann et al. 5849587 December 1998 Hanauske-Abel et al. 6020350 February 2000 Weidmann et al. 6046219 April 2000 Hanauske-Abel et al. 6080766 June 2000 Hanauske-Abel et al. 6566088 May 2003 Knight et al. 6589758 July 2003 Zhu 6930117 August 2005 Warshakoon et al. 6946479 September 2005 Warshakoon et al. 7183287 February 2007 Durley 7247632 July 2007 Warshakoon et al. 7247648 July 2007 Warshakoon et al. 7588924 September 2009 Evdokimov et al. 7790748 September 2010 Warshakoon et al. 7811595 October 2010 Kawamoto et al. 2002/0192737 December 2002 Kaelin, Jr. et al. 2003/0153503 August 2003 Klaus et al. 2003/0176317 September 2003 Guenzler-Pukall et al. 2004/0146964 July 2004 Maxwell et al. 2004/0254215 December 2004 Arend et al. 2006/0276477 December 2006 Klaus et al. 2007/0154482 July 2007 Sukhatme et al. 2007/0213335 September 2007 Fitch et al. 2007/0249550 October 2007 Sitkovsky 2007/0270407 November 2007 Warshakoon et al. 2007/0299086 December 2007 Kawamoto et al. 2008/0124740 May 2008 Evdokimov et al. 2008/0213404 September 2008 Johnson et al. 2008/0300262 December 2008 Snutch 2009/0082357 March 2009 Fitch et al. 2009/0093483 April 2009 Allen et al. 2011/0112055 May 2011 Gardner et al. 2433158 July 2002 2 443 714 March 1975 1 558 579 August 2005 WO 96/22021 July 1996 WO 96/22021 July 1996 WO 97/41103 November 1997 WO 02/074980 September 2002 WO 02/074981 September 2002 WO 03/028663 April 2003 WO 2004/035812 April 2004 WO 2005/007192 January 2005 WO 2005/118836 December 2005 WO 2006/114213 November 2006 WO 2007/038571 April 2007 WO 2007/047194 April 2007 WO 2007/070359 June 2007 WO 2007/082899 July 2007 WO 2007/103905 September 2007 WO 2007/136990 November 2007 WO 2007/150011 December 2007 WO 2008/089051 July 2008 WO 2008/089052 July 2008 WO 2008/130508 October 2008 WO 2008/130527 October 2008 WO 2008/137060 November 2008 WO 2008/144266 November 2008 WO 2009/019656 February 2009 WO 2009/037570 March 2009 WO 2009/039321 March 2009 WO 2009/039323 March 2009 WO 2009/043093 April 2009 WO 2009/049112 April 2009 WO 2009/067790 June 2009 WO 2009/070644 June 2009 WO 2009/073497 June 2009 WO 2009/073669 June 2009 WO 2009/086044 July 2009 WO 2009/086592 July 2009 WO 2009/089547 July 2009 |
| Other References: | Altschul et al., “Gapped BLAST and PSI-BLAST: A New Generation of Protein Database Search Programs,” Nucleic Acids Res., 25(27):3389-3402 (1997). cited by applicant Annex et al., “Growth Factor-Induced Therapeutic Angiogenesis in the Heart: Protein Therapy,” Cardiovascular Research, 65(3):649-655 (2005). cited by applicant Ardelt et al., “Estradiol Regulates Angiopoietin-1 mRNA Expression Through Estrogen Receptor-α in a Rodent Experimental Stroke Model,” Stroke, 36:337-341 (2005). cited by applicant Auerbach et al., “Angiogenesis Assays: A Critical Overview,” Clinical Chemistry, 49:32-40 (2003). cited by applicant Barany et al., “Solid-phase Peptide Synthesis: A Silver Anniversary Report,”Int. J Peptide Protein Res., 30(6):705-739 (1987). cited by applicant Bartlett et al., “Molecular Recognition in Chemical and Biological Problems,”Special Pub., Royal Chem. Soc., 78, 182-196 Caveat: A Program to Facilitate the Structure-derived Design of Biologically Active Molecules (Apr. 1989). cited by applicant Böhm, “The Computer Program LUDI: A New Method for the Novo Design of Enzyme Inhibitors,” J Computer-Aided Molecular Design, 6:61-78 (1992). cited by applicant Bussolino, “Molecular Mechanisms of Blood Vessel Formation,” Trends Biochem. Sci.,22(7):251-256 (1997). cited by applicant Cunliffe et al., “Novel Inhibitors of Prolyl 4-Hydroxylase 3 Inhibition by the Substrate Analogue N-Oxaloglycine and Its Derivatives,” J Med. Chem. 35:2652-2658 (1992). cited by applicant Elson et al., “Induction of Hypervascularity Without Leakage or Inflammation in Transgenic Mice Overexpressing Hypoxia-Indicible Factor-lα,” Genes & Dev.,15:2520-2532 (2001). cited by applicant Flower, “Modelling G-protein-coupled receptors for drug design,” Biochimica et Biophysica Acta, 1422:207-234 (1999). cited by applicant Folkman et al., “Tumor Angiogenesis,” The Molecular Basis of Cancer, Mendelsohn et al., eds., W. B. Saunders, Chapter 10, pp. 206-232 (1995). cited by applicant Franklin et al., “Approaches to the Design of Anti-Fibrotic Drugs,” Biochem. Soc. Trans., 19(4):812-5 (Nov. 1991). cited by applicant Goodford, “A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules,” J. Med. Chem., 28(7):849-857 (1985). cited by applicant Goodsell et al., “Automated Docking of Substrates to Proteins by Simulated Annealing,” Proteins: Structure, Function, and Genetics, 8:195-202 (1990). cited by applicant Jones et al., “Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation,” J. Mol. Biol., 245:43-53 (1995). cited by applicant Kaelin, “Proline Hydroxylation and Gene Expression,” Annu. Rev. Biochem., 74:115-125 (2005). cited by applicant Krantz, “Erythropoietin,” Blood, 77:419-434 (1991). cited by applicant Kuntz et al., “A Geometric Approach to Macromolecule—Ligand Interactions,” J. Mol. Biol., 161:269-288 (1982). cited by applicant Lee et al., “Structure of Human FIH-1 Reveals a Unique Active Site Pocket and Interaction Sites for HIF-1 and von Hippel Lindau,” JBC, 278:7558-7563 (2003). cited by applicant Li et al., “PR39, A Peptide Regulator of Angiogenesis,” Nat Med., 6(1):49-55 (2000). cited by applicant Mancini et al., “Effect of Erythropoietin on Exercise Capacity in Patients with Moderate to Severe Chronic Heart Failure,” Circulation, 107:294-299 (2003). cited by applicant McDonough et al., “Cellular Oxygen Sensing: Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2),” PNAS, 103(26):9814-9819 (2006). cited by applicant Miranker et al., “Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method,” Proteins: Structure, Function and Genetics, 11:29-34 (1991). cited by applicant Nguyen et al., “Cellular Interactions in Vascular Growth and Differentiation,” Int. Review of Cytology, 204:1-48 (2001). cited by applicant Nishibata et al., “Automatic Creation of Drug Candidate Structures Based on Receptor Structure. Starting Point for Artificial Lead Generation,” Tetrahedron, 47(43):8985-8990 (1991). cited by applicant O'Reilly et al., “Angiostatin: A Novel Angiogenesis Inhibitor that Mediates the Suppression of Metastases by a Lewis Lung Carcinoma,” Cell, 79:315-328 (1994). cited by applicant O'Reilly et al., “Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth,” Cell, 88:277-285 (1997). cited by applicant Peyssonnaux et al., “HIF-1α Expression Regulates the Bactericidal Capacity of Phagocytes,” J. Clinical Invest., 115(7):1806-1815. cited by applicant Schoneberg et al., “Structural Basis of G Protein-Coupled Receptor Function,” Molecular and Cellular Endocrinology, 151:181-193 (1999). cited by applicant Semenza, “Signal Transduction to Hypoxia-inducible Factor 1,” Biochem. Pharmacol, 64:993-998 (2002). cited by applicant Semenza, “Regulation of Erythropoietin Porduction: New Insights into Molecular Mechanisms of Oxygen Homeostasis,” Hematol. Oncol. Clin. North Am., 8:863-884 (1994). cited by applicant Semenza et al., “Transcriptional Regulation of Genes Encoding Glycolytic Enzymes by Hypoxia-Inducible Factor 1,” J. Biol. Chem., 269:23757-23763 (1994). cited by applicant Sexton, “Recent advances in our understanding of peptide hormone receptors and RAMPS,” Current Opinion in Drug Discovery and Development, 2(5):440-448 (1999). cited by applicant Sheehan, “3-Hydroxypicolinic Acid and Some of its Derivatives,” J. Organic Chemistry 31(3):636-638 (1996). cited by applicant Teicher et al., “Potentiation of Cytotoxic Cancer Therapies by TNP-470 Alone and with Other Anti-Angiogenic Agents,” Int. J. Cancer, 57:920-925 (1994). cited by applicant Vincent et al., “Angiogenesis is Induced in a Rabbit Model of Hindlimb Ischemia by Naked DNA Encoding an HIF-1α/VP16 Hybrid Transcription Factor,” Circulation, 102:2255-2261 (2000). cited by applicant Warnecke et al., “Activation of the Hypoxia-Inducible Factor Pathway and Stimulation of Angiogenesis by Application of Prolyl Hydroxylase Inhibitors,” FASEB Journal, 17:1186-1188 (2003). cited by applicant Warner et al., “Epolones induce erythropoietin expression via hypoxia-inducible factor-1α activation,” Blood, 96(4): 1558-1565 (2000). cited by applicant Wax et al., “SM-20 is a Novel 20-kd Protein Whose Expression in the Arterial Wall is Restricted to Smooth Muscle,” Lab. Invest., 74(4):797-808 (1996). cited by applicant Weidner et al., “Tumor Angiogenesis and Metastasis—Correlation in Invasive Breast Carcinoma,” New Eng. J Med., 324(1):1-8 (1991). cited by applicant Wright et al., “Activation of the Prolyl Hydroxylase Oxygen-Sensor Results in Induction of GLUT1, Heme Oxygenase-1, and Nitric-Oxide Synthase Proteins and Confers Protection from Metabolic Inhibition to Cardiomyocytes,” J. Bio. Chem., 278(22):20235-20239 (2003). cited by applicant Dannhardt et al., “Z-s-Z-Enaminone und—thione mit semicyclishcher C=C-Bindung,” Chemiker-Zeitung, 111(7-8):237-40 (1987) (translation provided). cited by applicant Muellner, F.W. et al., “The Synthesis of 1,4-ethano-1,2,3,4-tetrahydroisoquinolines as rigid analogues of adrenergic agents,” J. Heterocyclic Chemistry, (1983), 20, 1581-1584. cited by applicant Pedersen, et al., “Studies on Organophosphorus compound XX—Synthesis of Thioketones,” Bulletin Des Societes Chimiques Belges, 87(3):223- (1978). cited by applicant Posner, G.H. et al., “Diels-Alder cycloadditions using nucleophilic 2-pridones. Regiocontrolled and stereocontrolled synthesis of unsaturated, bridged, bicyclic lactams,” J. Organic Chemistry, (1992), 57:15, 4088-4097. cited by applicant |
| Assistant Examiner: | Sackey, Ebenezer O |
| Primary Examiner: | Wilson, James O |
| Attorney, Agent or Firm: | Echler, Richard S. |
| رقم الانضمام: | edspgr.08536181 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |