Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship

Bioorganic and Medicinal Chemistry

Volumn 19, Issue 3, 2011, Pages 1242-1255

  Xie, Jin ^a   Poda, Gennadiy I ^a   Hu, Yiding ^a   Chen, Natalie X ^a   Heier, Richard F ^a   Wolfson, Serge G ^a   Reding, Matthew T ^a   Lennon, Patrick J ^a   Kurumbail, Ravi G ^a   Selness, Shaun R ^a   Li, Xiong ^a   Kishore, Nandini N ^a   Sommers, Cynthia D ^a   Christine, Lori ^a   Bonar, Sheri L ^a   Venkatraman, Neetu ^a   Mathialagan, Sumathy ^a   Brustkern, Sarah J ^a   Huang, Horng Chih ^a  

^a PFIZER INC   (United States)

Author keywords

Asthma; COPD; DOA; IKK 2; Inhaled approach; Inhibitors; Potent; Selective

Indexed keywords

1 (3 CHLORO 4 HYDROXYPHENYL) 8 {[5 CHLORO 2 (4 METHYLPIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 1 (4 CHLORO 3 HYDROXYPHENYL) 8 {[5 CHLORO 2 (4 METHYLPIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 1 (4 {[3 CARBAMOYL 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOL 8 YL]CARBAMOYL} 5 CHLOROPYRIDIN 2 YL) 4 [(1 METHYL 1H PYRAZOL 4 YL)METHYL]PIPERAZINE 2 CARBOXYLIC ACID; 4 (4 {[3 CARBAMOYL 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOL 8 YL]CARBAMOYL} 5 CHLOROPYRIDIN 2 YL) 1 [(1 METHYL 1H PYRAZOL 4 YL)METHYL]PIPERAZINE 2 CARBOXYLIC ACID; 8 (5 CHLORO 2 (4 METHYLPIPERAZIN 1 YL)ISONICOTINAMIDO) 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 ({5 CHLORO 2 [4 ({1 [2 (DIMETHYLAMINO) 2 OXOETHYL] 1H PYRAZOL 4 YL}METHYL)PIPERAZIN 1 YL]ISONICOTINOYL}AMINO) 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 ({5 CHLORO 2 [4 ({1 [2 (ISOPROPYLAMINO) 2 OXOETHYL] 1H PYRAZOL 4 YL}METHYL)PIPERAZIN 1 YL]ISONICOTINOYL}AMINO) 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 ({5 CHLORO 2 [4 ({1 [3 (2 METHOXYETHOXY)PROPYL] 1H PYRAZOL 4 YL}METHYL)PIPERAZIN 1 YL]ISONICOTINOYL}AMINO) 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 ({5 CHLORO 2 [4 ({1 [3 (DIMETHYLAMINO)PROPYL] 1H PYRAZOL 4 YL}METHYL)PIPERAZIN 1 YL]ISONICOTINOYL}AMINO) 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 [(5 CHLORO 2 {(3) 3 METHYL 4 [(1 METHYL 1H PYRAZOL 4 YL)METHYL]PIPERAZIN 1 YL}ISONICOTINOYL)AMINO] 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 [(5 CHLORO 2 {4 [(1 METHYL 1H PYRAZOL 4 YL)METHYL]PIPERAZIN 1 YL}ISONICOTINOYL)AMINO] 1 (3 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 [(5 CHLORO 2 {4 [(1 METHYL 1H PYRAZOL 4 YL)METHYL]PIPERAZIN 1 YL}ISONICOTINOYL)AMINO] 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 [(5 CHLORO 2 {4 [(1 {2 [(2 METHOXYETHYL)AMINO] 2 OXOETHYL} 1H PYRAZOL 4 YL)METHYL]PIPERAZIN 1 YL}ISONICOTINOYL)AMINO] 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G] INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 METHYLPIPERAZIN 1 YL)ISONICOTINOYL] AMINO} 1 (3 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 METHYLPIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 1 (3 HYDROXYPHENYL) 4,5 DIHYDRO 1H BENZO[G] INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 METHYLPIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 1 (3,4 DIFLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 METHYLPIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 1 (4 HYDROXYPHENYL) 4,5 DIHYDRO 1H BENZO[G] INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 METHYLPIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 1 (4 METHOXYPHENYL) 4,5 DIHYDRO 1H BENZO[G] INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 {[1 (2 CYANOETHYL) 1H PYRAZOL 4 YL]METHYL}PIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 {[1 (2 {[2 (METHYLTHIO)ETHYL] AMINO} 2 OXOETHYL) 1H PYRAZOL 4 YL]METHYL}PIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 {[1 (3 HYDROXYPROPYL) 1H PYRAZOL 4 YL]METHYL}PIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; 8 {[5 CHLORO 2 (4 {[1 (3 METHOXYPROPYL) 1HPYRAZOL 4 YL]METHYL}PIPERAZIN 1 YL)ISONICOTINOYL]AMINO} 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOLE 3 CARBOXAMIDE; AMIDE; AMINOPYRIDINE DERIVATIVE; ETHYL 3 [4 ({4 [4 ({[3 (AMINOCARBONYL) 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOL 8 YL]AMINO}CARBONYL) 5 CHLOROPYRIDIN 2 YL]PIPERAZIN 1 YL}METHYL) 1H PYRAZOL 1 YL]PROPANOATE; ETHYL [4 ({4 [4 ({[3 (AMINOCARBONYL) 1 (3 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOL 8 YL]AMINO} CARBONYL) 5 CHLOROPYRIDIN 2 YL]PIPERAZIN 1 YL}METHYL) 1H PYRAZOL 1 YL]ACETATE; ETHYL [4 ({4 [4 ({[3 (AMINOCARBONYL) 1 (4 FLUOROPHENYL)4,5 DIHYDRO 1H BENZO[G]INDAZOL 8 YL]AMINO}CARBONYL) 5 CHLOROPYRIDIN 2 YL]PIPERAZIN 1 YL}METHYL) 1H PYRAZOL 1 YL]ACETATE; I KAPPA B KINASE INHIBITOR; METHYL [4 ({4 [4 ({[3 (AMINOCARBONYL) 1 (4 FLUOROPHENYL) 4,5 DIHYDRO 1H BENZO[G]INDAZOL 8 YL]AMINO}CARBONYL) 5 CHLOROPYRIDIN 2 YL]PIPERAZIN 1 YL}METHYL) 1H PYRAZOL 1 YL]ACETATE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; ASTHMA; CHRONIC OBSTRUCTIVE LUNG DISEASE; CONTROLLED STUDY; DRUG CLEARANCE; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENCY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, INHALATION; AMINOPYRIDINES; ASTHMA; BINDING, COMPETITIVE; DRUG DESIGN; HEK293 CELLS; HUMANS; I-KAPPA B KINASE; INDAZOLES; ISONICOTINIC ACIDS; MICROSOMES, LIVER; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MOLECULAR TARGETED THERAPY; NIACINAMIDE; PHENETHYLAMINES; POTASSIUM CHANNEL BLOCKERS; PROTEIN KINASE INHIBITORS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; PYRAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 79551496434     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2010.12.027     Document Type: Article

References (42)

1. I.M. Adock, K.F. Chung, G. Caramori, and K. Ito Eur. J. Pharmacol. 533 2006 118
2. P. Barnes Pharmacol. Ther. 109 2006 238
3. A.S. Baldwin Jr J. Clin. Invest. 107 2001 3
4. G. Bonizzi, and M. Karin Treands Immunol. 25 2004 280
5. S. Ghosh, and M. Karin Cell 109 2002 S81
6. U. Swenftleben, and M. Karin Crit. Care Med. 30 2002 S18
7. A.C. Castro, L.C. Dang, F. Soucy, L. Grenier, H. Mazdiyasni, and M. Hottelet Bioorg. Med. Chem. Lett. 13 2003 2419
8. M. Karin, Y. Yamamoto, and Q.M. Wang Nat. Rev. Drug Disc. 3 2004 17
9. B.G. Cosio, B. Mann, K. Ito, E. Jazrawi, P.J. Barnes, and K.F. Chung Am. J. Respir. Crit. Care Med. 170 2004 141
10. Baxter, A.; Brough, S.; Faull, A.; Johnstone, C.; Mcinally, T.; PCT Int. Appl. WO 0158890 A1, 2001.
11. Griffiths, D.; Johnstone, C., 2003, WO 2003010163 A1 20030206.
12. A. Baxter, S. Brough, A. Cooper, E. Floettmann, S. Foster, C. Harding, J. Kettle, T. McInally, C. Martin, M. Mobbs, M. Needham, P. Newham, S. Paine, St. St-Gallay, S. Salter, J. Unitt, and T. Xue Bioorg. Med. Chem. Lett 14 2004 2817
13. D. Bonafoux, S. Bonar, L. Christine, M. Clare, A. Donnelly, J. Guzova, N. Kishore, P. Lennon, A. Libby, S. Mathialagan, W. McGhee, S. Rouw, C. Sommers, M. Tollefson, C. Tripp, R. Weier, S. Wolfson, and Y. Min Bioorg. Med. Chem. Lett. 15 2005 2870
14. Kerns, J. K.; PCT Int. Appl. WO 2007076286 A2, 2007.
15. Kerns, J. K.; Lindenmuth, M.; Lin, X.; Nie, H.; Thomas, S. M., PCT Int. Appl. WO 034317 A2, 2006.
16. Deng, J.; Kerns, J. K.; Jin, Q.; Lin, G.; Lin, X.; Lindenmuth, M.; Neipp, C. E.; Nie, H. T.; Sonia, M.; Widdowson, K. L., PCT Int. Appl. WO 005534 A2, 2007.
17. Clare, M.; Fletcher, T. R.; Hamper, B. C.; Hanson, G. A.; Heier, R. F.; Huang, H.; Lennon, P. J.; Oburn, D. S.; Reding, M. T.; Stealey, M. A.; Wolfson, S. G.; Xie, J., PCT Int. Appl. WO 037797 A1, 2005.
18. Morey, J. V.; Christopher, J. A. PCT Int. Appl. WO 025575 A1, 2007.
19. J.A. Christopher, B.G. Avitabile, P. Bamborough, A.C. Champigny, G.J. Cutler, S.L. Dyos, K.G. Grace, J.K. Kerns, J.D. Kitson, G.W. Mellor, J.V. Morey, M.A. Morse, C.F. O'Malley, C.B. Patel, N. Probst, W. Rumsey, C.A. Smith, and M.J. Wilson Bioorg. Med. Chem. Lett. 17 2007 3972
20. R. Waelchli, B. Bollbuck, C. Bruns, T. Buhl, J. Eder, R. Feifel, R. Hersperger, P. Janser, L. Revesz, H.-G. Zerwes, and A. Schlapbach Bioorg. Med. Chem. Lett. 16 2006 108
21. Murata, T.; Sakakibara, S.; Yoshino, T.; Ikegami, Y.; Masuda, T.; Shimada, M.; Shintani, T.; Shimazaki, M.; Lowinger, T. B.; Ziegelbauer, K. B.; Fuchikami, K.; Umeda, M.; Komura, H.; Yoshida, N. WO 03024935 A2, 2002.
22. T. Murata, M. Shimada, S. Sakakibara, T. Yoshino, H. Kadono, T. Masuda, M. Shimazaki, T. Shintani, K. Fuchikami, K. Sakai, H. Inbe, K. Takeshita, T. Niki, M. Umeda, K.B. Bacon, K.B. Ziegelbauer, and T.B. Lowinger Bioorg. Med. Chem. Lett. 13 2003 913
23. A.H. Binghama, R.J. Davenport, R. Fosbeary, L. Gowersa, R.L. Knighta, C. Lowea, D.A. Owena, D.M. Parrya, and W.R. Pitt Bioorg. Med. Chem. Lett. 18 2008 3622
24. Okamoto, Y.; Kubota, H.; Sato, I.; Hattori, K.; Kanayama, T.; Yokoyama, K.; Terai, Y.; Takeuchi, M. PCT Int. Appl. WO 100341 A1, 2005.
25. Clare, M.; Hagen, T. J.; Houdek, S. C.; Lennon, P. J.; Weier, R. M.; Xu, X., PCT Int. Appl. WO 040133 A1, 2005.
26. A.H. Bingham, R.J. Davenport, R. Fosbeary, L. Gowers, R.L. Knight, C. Lowe, D.A. Owen, D.M. Parry, and W.R. Pitt Bioorg. Med. Chem. Lett. 18 2008 3622
27. A.C. Castro, L.C. Dang, F. Soucy, L. Grenier, H. Mazdiyasni, M. Hottelet, L. Parent, C. Pien, V. Palombella, and J. Adams Bioorg. Med. Chem. Lett. 13 2003 2419
28. Bamborough, P.; Barker, M. D.; Campos, A. A.; Cousins, R. C.; Faulder, P.; Hobbs, H.; Holmes, D. S.; Johnston, M. J.; Liddle, J. P., Jeremy J.; Pritchard, J. M.; Whitworth, C., PCT Int. Appl. WO 2008034860 A1, 2008.
29. M. Belema, A. Bunker, V.N. Nguyen, F. Beaulieu, C. Ouellet, Y. Qiu, Y. Zhang, A. Martel, J.R. Burke, K.W. McIntyre, M.A. Pattoli, C. Daloisio, K.M. Gillooly, W.J. Clarke, P.J. Brassil, F.C. Zusi, and D.M. Vyas Bioorg. Med. Chem. Lett. 17 2007 4284
30. D. Bonafoux, S. Bonar, M. Clare, A. Donnelly, J. Guzova, N. Kishore, P. Lennon, A. Libby, S. Mathialagan, W. McGhee, S. Rouw, C. Sommers, M. Tollefson, C. Tripp, R. Weier, S. Wolfson, and H.-C. Huang Bioorg. Med. Chem. Lett. 18 2010 413
31. G. Mbalaviele, C.D. Sommers, S.L. Bonar, S. Mathialagan, J.F. Schindler, J.A. Guzova, A.F. Shaffer, M.A. Melton, L.J. Christine, C.S. Tripp, P.-C. Chiang, D.C. Thompson, Y. Hu, and N. Kishore J. Pharmacol. Exp. Ther. 329 2009 14
32. C.D. Sommers, J.M. Thompson, J.A. Guzova, S.L. Bonar, R.K. Rader, S. Mathialagan, N. Venkatraman, V.W. Holway, L.E. Kahn, G. Hu, D.S. Garner, H.-C. Huang, P.-C. Chiang, J.F. Schindler, Y. Hu, D.M. Meyer, and N.N. Kishore J. Pharmacol. Exp. Ther. 330 2009 377
33. Bergmanis, A. A.; Bonafoux, D.; Clare, M.; Crich, J. Z.; Fletcher, T. R.; Geng, L.; Hagen, T. J.; Hamper, B. C.; Hanson, G. J.; Houdek, S. C.; Huang, H.; Iula, D. M.; Koszyk, F. J.; Lennon, P. J.; Liao, S.; Liao, S.; Metz, S.; Mohler, S. B.; Nguyen, M.; Oburn, D. S.; Owen, T. J.; Partis, R. A.; Scates, A. M.; Stealey, M. A.; Tollefson, M. B.; Vazquez, M. L.; Weier, R. M.; Wolfson, S. G.; Xu, X. PCT Int. WO 200324935, 2003.
34. Z.R. Tayab, and G. Hochhaus Expert Opin. Drug Deliv. 2 2005 519
35. N. Kishore, Q.K. Huynh, S. Mathialagan, T. Hall, R. Rouw, D. Creely, G. Lange, J. Caroll, B. Reitz, A. Donnelly, H. Boddupalli, R.G. Combs, K. Kretzmer, and C.S. Tripp J. Biol. Chem. 277 2002 13840
36. Q.K. Huynh, H. Boddupalli, S.A. Rouw, C.M. Koboldt, T. Hall, C. Sommers, S.D. Hauser, J.L. Pierce, R.G. Combs, B.A. Reitz, J.A. Diaz-collier, R.A. Weinberg, B.L. Hodd, B.F. Kilpatrick, and C.S. Tripp J. Biol. Chem. 275 2000 25883
37. F. Chen, V. Castranova, X. Shi, and L.M. Demers Clin. Chem. 45 1999 7
38. S. Ghosh, M.J. May, and E.B. Kopp Annu. Rev. Immunol. 16 1998 225
39. M. Karin Oncogene 18 1999 6867
40. S. Mathialagan, G.I. Poda, R.G. Kurumbail, S.R. Selness, T. Hall, B.A. Reitz, R.A. Weinberg, N. Kishore, and G. Mbalaviele Protein Expr. Purif. 72 2010 254
41. Poda, G.; Clare, M.; Kurumbail, R. G., unpublished data.
42. W. Sherman, T. Day, M.P. Jacobson, R.A. Friesner, and R. Farid J. Med. Chem. 49 2006 534