Benzimidazole-2-pyrazole HIF prolyl 4-hydroxylase inhibitors as oral erythropoietin secretagogues

ACS Medicinal Chemistry Letters

Volumn 1, Issue 9, 2010, Pages 526-529

  Rosen, Mark D ^a   Venkatesan, Hariharan ^a   Peltier, Hillary M ^a   Bembenek, Scott D ^a   Kanelakis, Kimon C ^a   Zhao, Lucy X ^a   Leonard, Barry E ^a   Hocutt, Frances M ^a   Wu, Xiaodong ^a   Palomino, Heather L ^a   Brondstetter, Theresa I ^a   Haugh, Peter V ^a   Cagnon, Laurence ^a   Yan, Wen ^a   Liotta, Lisa A ^a   Young, Andrew ^a   Mirzadegan, Tara ^a   Shankley, Nigel P ^a   Barrett, Terrance D ^a   Rabinowitz, Michael H ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

anemia; epo; erythropoietin; erythropoietin stimulating agents; HIF; hypoxia inducible factor; PHD inhibitors; Prolyl 4 hydroxylase inhibitors

Indexed keywords

BENZIMIDAZOLE 2 PYRAZOLE HYPOXIA INDUCIBLE FACTOR PROLYL 4 HYDROXYLASE INHIBITOR; CARBOXYLIC ACID DERIVATIVE; ERYTHROPOIETIN; PROCOLLAGEN PROLINE 2 OXOGLUTARATE 4 DIOXYGENASE; UNCLASSIFIED DRUG;

ARTICLE; DRUG DEVELOPMENT; DRUG EFFICACY; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITION; HORMONE RELEASE; HUMAN; HUMAN CELL; HYPOXIA; IN VIVO STUDY; PRIORITY JOURNAL;

EID: 78650211341     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml100198y     Document Type: Article

References (29)

1. 2 sensing Science 2001, 292, 464-468
2. Berra, E.; Benizri, E.; Ginouves, A.; Volmat, V.; Roux, D.; Pouyssegur, J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia EMBO J. 2003, 22, 4082-4090
3. Schofield, C. J.; Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases Nat. Rev. Mol. Cell Biol. 2004, 40, 343-354
4. Webb, J. D.; Coleman, M. L.; Pugh, C. W. Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing Cell. Mol. Life Sci. 2009, 66, 3539-3554
5. Salceda, S.; Caro, J. Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes J. Biol. Chem. 1997, 272, 22642-22647
6. Wenger, R. H.; Stiehl, D. P.; Camenisch, G. Integration of oxygen signaling at the consensus HRE Science Signal 2005, 306, re12
7. Ivan, M.; Harris, A. L.; Martelli, F.; Kulshreshtha, R. Hypoxia response and microRNAs: no longer two separate worlds J. Cell. Mol. Med. 2008, 12, 1426-1431
8. 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 tissue Acta Physiol. 2009, 195, 407-414
9. Siddiq, A.; Aminova, L. R.; Ratan, R. R. Hypoxia inducible factor prolyl 4-hydroxylase enzymes: Center stage in the battle against hypoxia, metabolic compromise, and oxidative stress Neurochem. Res. 2007, 32, 931-946
10. Review: Yan, L.; Colandrea, V. J.; Hale, J. J. Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia Expert Opin. Ther. Pat. 2010, 20, 1219-1245
11. Rabinowitz, M. H.; Barrett, T. D.; Rosen, M. D.; Venkatesan, H. Inhbitors of HIF Prolyl Hydroxylase. In Annual Reports in Medicinal Chemistry; Macor, J. E.; Robichaud, A. J.; Stamford, A. W.; Weinstein, D.; McAlpine, S.; Primeau, J.; Lowe, J.; Desai, M. C., Eds.; Elsevier: London, 2010; Vol. 45, in press.
12. 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
13. Mecinovic, J.; Loenarz, C.; Chowdhury, R.; Schofield, C. J. 2-Oxoglutarate analogue inhibitors of prolyl hydroxylase domain 2 Bioorg. Med. Chem. Lett. 2009, 19, 6192-6195
14. Frohn, M.; Viswanadhan, V.; Pickrell, A. J.; Golden, J. E.; Muller, K. M.; Burli, 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 Bioorg. Med. Chem. Lett. 2008, 18, 5023-5026
15. 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 hydroxyl-thiazoles as HIF-α prolyl hydroxylase inhibitors: SAR, synthesis, and modeling evaluation Bioorg. Med. Chem. Lett. 2008, 18, 3925-3928
16. 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 (Pubitemid 44415435)
17. 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 (Pubitemid 44415448)
18. 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 (Pubitemid 44415469)
19. Mole, D. R.; Schlemminger, I.; McNeill, L. A.; Hewitson, K. S.; Pugh, C. W.; Ratcliffe, P. J.; Schofield, C. J. 2-Oxoglutarate analogue inhibitors of HIF prolyl hydroxylase Bioorg. Med. Chem. Lett. 2003, 13, 2677-2680
20. Melnikova, I. Anaemia therapies Nature Rev. Drug Discovery 2006, 5, 627-628
21. Clinicaltrials.gov identifiers: NCT00750256, NCT00761657, NCT00840320, and NCT01083888.
22. Wang, J.; Buss, J. L.; Chen, G.; Ponka, P.; Pantopoulos, K. The prolyl 4-hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate generates effective iron deficiency in cultured cells FEBS Lett. 2002, 529, 309-312
23. Kanelakis, K. C.; Palomino, H. L.; Li, L.; Wu, J.; Yan, W.; Rosen, M. D.; Rizzolio, M. C.; Triveda, M.; Morton, M. F.; Yang, Y.; Venkatesan, H.; Rabinowitz, M. H.; Shankley, N. P.; Barrett, T. B. Characterization of a robust enzymatic assay for inhibitors of 2-oxoglutarate-dependent hydroxylases J. Biomol. Screening 2009, 14, 627-635
24. Ennis, B. C.; Holan, G.; Samuel, E. L. 2-(Trihalomethyl)benzazoles. III. Reactions of 2-(trichloromethyl)benzimidazole with nucleophiles J. Chem. Soc. C 1967, 30-33
25. Breuer, W.; Epsztejn, S.; Millgram, P.; Cabantchik, I. Z. Transport of iron and other transition metals into cells as revealed by a fluorescent probe Am. J. Physiol. Cell Physiol. 1995, 268, 1354-1361
26. Zorc, B. Peptidomimetics Farm. Glas. 2008, 64, 113-121
27. McDonough, M. A.; Li, V.; Flashman, E.; Rasheduzzaman, C.; 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
28. Evodkimov, A. G.; Walter, R. L.; Mekel, M.; Pokross, M. E.; Kawamoto, R.; Boyer, A. RCSB Protein Data Bank ID: 2HBT, 2006.
29. The coordinates have been deposited with the RSCB Protein Data Bank. PHD2/2OG, PDB ID 3OUJ; PHD2/ 3b, 3OUI; and PHD2/ 6d, 3OUH.