A novel inhibitor of 1-KappaB kinase beta ameliorates experimental arthritis through downregulation of proinflammatory cytokines in arthritic joints

Biological and Pharmaceutical Bulletin

Volumn 37, Issue 1, 2014, Pages 87-95

  Tanaka, Shinji ^a   Toki, Tadashi ^a   Yokoyama, Mika ^a   Shimizu, Hiroki ^a   Yamasaki, Tomonori ^a   Yoneda, Yoshiyuki ^a   Muro, Fumihito ^a   Yasukochi, Takanori ^a   Iimura, Shin ^a   Morishita, Kaoru ^a  

^a DAIICHI SANKYO CO   (Japan)

Author keywords

Arthritis; Inhibitor; Inhibitor of kappaB kinase beta; Nuclear factor KappaB; Tumor necrosis factor alpha

Indexed keywords

4 [6 (CYCLOBUTYLAMINO)IMIDAZO[1,2 BETA]PYRIDAZIN 3 YL] 2 FLUORO N [(4 FLUOROPYRROLIDIN 2 YL)METHYL]BENZAMIDE; GELATINASE B; I KAPPA B KINASE BETA; I KAPPA B KINASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 6; OSTEOCLAST DIFFERENTIATION FACTOR; STROMELYSIN; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; 4-(6-(CYCLOBUTYLAMINO)IMIDAZO(1,2-B)PYRIDAZIN-3-YL)-2-FLUORO-N-((4-FLUOROPYRROLIDIN-2-YL)METHYL)BENZAMIDE; 4 (6 (CYCLOBUTYLAMINO)IMIDAZO(1,2 B)PYRIDAZIN 3 YL) 2 FLUORO N ((4 FLUOROPYRROLIDIN 2 YL)METHYL)BENZAMIDE; ANTIRHEUMATIC AGENT; AUTACOID; BENZAMIDE DERIVATIVE; CYTOKINE; FUSED HETEROCYCLIC RINGS; I KAPPA B; I KAPPA B KINASE; NF KAPPAB INHIBITOR ALPHA; NF-KAPPAB INHIBITOR ALPHA; PROTEIN KINASE INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RELEASE; DOWN REGULATION; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; EXPERIMENTAL ARTHRITIS; FEMALE; HUMAN; HUMAN CELL; MALE; MOUSE; NONHUMAN; PAW EDEMA; PROTEIN DEGRADATION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; ANIMAL; BAGG ALBINO MOUSE; BIOSYNTHESIS; DBA MOUSE; DRUG ANTAGONISM; DRUG EFFECT; GENE EXPRESSION; JOINT; METABOLISM; PATHOLOGY; PHOSPHORYLATION; RHEUMATOID ARTHRITIS; TISSUE DISTRIBUTION;

ANIMALS; ANTIRHEUMATIC AGENTS; ARTHRITIS, EXPERIMENTAL; ARTHRITIS, RHEUMATOID; BENZAMIDES; CYTOKINES; DOWN-REGULATION; FEMALE; GENE EXPRESSION; HETEROCYCLIC COMPOUNDS, 2-RING; I-KAPPA B KINASE; I-KAPPA B PROTEINS; INFLAMMATION MEDIATORS; INTERLEUKIN-6; JOINTS; MALE; MICE; MICE, INBRED BALB C; MICE, INBRED DBA; NF-KAPPA B; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; TISSUE DISTRIBUTION; TUMOR NECROSIS FACTOR-ALPHA;

EID: 84892596879     PISSN: 09186158     EISSN: 13475215     Source Type: Journal    
DOI: 10.1248/bpb.b13-00628     Document Type: Article

References (49)

1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature, 423, 356-361 (2003)
2. Brown KD, Claudio E, Siebenlist U. The roles of the classical and alternative nuclear factor-kappaB pathways: Potential implicationsfor autoimmunity and rheumatoid arthritis. Arthritis Res. Ther., 10, 212 (2008)
3. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N. Engl. J. Med., 344, 907-916 (2001)
4. Eastgate JA, Wood NC, Di Giovine FS, Symons JA, Grinlinton FM, Duff GW. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet, 332, 706-709 (1988)
5. Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum., 31, 784-788 (1988).
6. Tetta C, Camussi G, Modena V, Di Vittorio C, Baglioni C. Tumour necrosis factor in serum and synovial fluid of patients with active and severe rheumatoid arthritis. Ann. Rheum. Dis., 49, 665-667 (1990)
7. Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat. Rev. Rheumatol., 5, 578-582 (2009)
8. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu. Rev. Immunol., 12, 141-179 (1994)
9. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev., 18, 2195-2224 (2004)
10. Perkins ND. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat. Rev. Mol. Cell Biol., 8, 49-62 (2007).
11. Senftleben U, Karin M. The IKK/NF-kappaB pathway. Crit. Care Med., 30 (Suppl.), S18-S26 (2002)
12. Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-kappaB and IkappaB proteins: Implications in cancer and inflammation. Trends Biochem. Sci., 30, 43-52 (2005)
13. Tak PP, Firestein GS. NF-kappaB: A key role in inflammatory diseases. J. Clin. Invest., 107, 7-11 (2001)
14. DiDonato J, Mercurio F, Rosette C, Wu-Li J, Suyang H, Ghosh S, Karin M. Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Mol. Cell. Biol., 16, 1295-1304 (1996)
15. Makarov SS. NF-kappa B in rheumatoid arthritis: A pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res., 3, 200-206 (2001).
16. Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell. Signal., 13, 85-94 (2001)
17. Karin M. How NF-kappaB is activated: The role of the IkappaB kinase (IKK) complex. Oncogene, 18, 6867-6874 (1999)
18. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell, 109 (Suppl.), S81-S96 (2002)
19. Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, Johnson R, Karin M. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J. Exp. Med., 189, 1839-1845 (1999).
20. Mbalaviele G, Sommers CD, Bonar SL, Mathialagan S, Schindler JF, Guzova JA, Shaffer AF, Melton MA, Christine LJ, Tripp CS, Chiang PC, Thompson DC, Hu Y, Kishore N. A novel, highly selective, tight binding IkappaB kinase-2 (IKK-2) inhibitor: A tool to correlate IKK-2 activity to the fate and functions of the components of the nuclear factor-kappaB pathway in arthritis-relevant cells and animal models. J. Pharmacol. Exp. Ther., 329, 14-25 (2009)
21. McIntyre KW, Shuster DJ, Gillooly KM, Dambach DM, Pattoli MA, Lu P, Zhou XD, Qiu Y, Zusi FC, Burke Jr. A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum., 48, 2652-2659 (2003).
22. Podolin PL, Callahan JF, Bolognese BJ, Li YH, Carlson K, Davis TG, Mellor GW, Evans C, Roshak AK. Attenuation of murine collagen- induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]- 5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell proliferation. J. Pharmacol. Exp. Ther., 312, 373-381 (2005)
23. Schopf L, Savinainen A, Anderson K, Kujawa J, DuPont M, Silva M, Siebert E, Chandra S, Morgan J, Gangurde P, Wen D, Lane J, Xu Y, Hepperle M, Harriman G, Ocain T, Jaffee B. IKKbeta inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis. Arthritis Rheum., 54, 3163-3173 (2006)
24. Shimizu H, Yamasaki T, Yoneda Y, Muro F, Hamada T, Yasukochi T, Tanaka S, Toki T, Yokoyama M, Morishita K, Iimura S. Discovery of imidazo[1,2-b] pyridazines as IKKbeta inhibitors. Part 3: Exploration of effective compounds in arthritis models. Bioorg. Med.Chem. Lett., 21, 4550-4555 (2011)
25. Wen D, Nong Y, Morgan JG, Gangurde P, Bielecki A, Dasilva J, Keaveney M, Cheng H, Fraser C, Schopf L, Hepperle M, Harriman G, Jaffee BD, Ocain TD, Xu Y. A selective small molecule IkappaB Kinase beta inhibitor blocks nuclear factor kappaB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes, and mast cells. J. Pharmacol. Exp. Ther., 317, 989-1001 (2006).
26. Shimizu H, Tanaka S, Toki T, Yasumatsu I, Akimoto T, Morishita K, Yamasaki T, Yasukochi T, Iimura S. Discovery of imidazo[1,2-b] pyridazine derivatives as IKKbeta inhibitors. Part 1: Hit-to-lead study and structure-activity relationship. Bioorg. Med. Chem. Lett., 20, 5113-5118 (2010).
27. Shimizu H, Yasumatsu I, Hamada T, Yoneda Y, Yamasaki T, Tanaka S, Toki T, Yokoyama M, Morishita K, Iimura S. Discovery of imidazo[1,2-b]pyridazines as IKKbeta inhibitors. Part 2: Improvement of potency in vitro and in vivo. Bioorg. Med. Chem. Lett., 21, 904-908 (2011)
28. Hawiger J, Veach RA, Liu XY, Timmons S, Ballard DW. IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. Blood, 94, 1711-1716 (1999).
29. Binstadt BA, Patel PR, Alencar H, Nigrovic PA, Lee DM, Mahmood U, Weissleder R, Mathis D, Benoist C. Particularities of the vasculature can promote the organ specificity of autoimmune attack. Nat. Immunol., 7, 284-292 (2006).
30. Blanchet MR, Gold M, Maltby S, Bennett J, Petri B, Kubes P, Lee DM, McNagny KM. Loss of CD34 leads to exacerbated autoimmune arthritis through increased vascular permeability. J. Immunol., 184, 1292-1299 (2010)
31. Cloutier N, Pare A, Farndale RW, Schumacher HR, Nigrovic PA, Lacroix S, Boilard E. Platelets can enhance vascular permeability. Blood, 120, 1334-1343 (2012).
32. Stewart CF, Christensen ML, Evens RP, Cremer M, Evans WE. Influence of concomitant aspirin or prednisone on methotrexate synovial fluid concentration. J. Pharmacol. Exp. Ther., 243, 131-137 (1987)
33. Joosten LA, Helsen MM, van de Loo FA, van den Berg WB. Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. A comparative study using anti-TNF alpha, anti- IL-1 alpha/beta, and IL-1Ra. Arthritis Rheum., 39, 797-809 (1996).
34. Williams RO, Feldmann M, Maini RN. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. U.S.A., 89, 9784-9788 (1992)
35. Wooley PH, Dutcher J, Widmer MB, Gillis S. Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice. J. Immunol., 151, 6602-6607 (1993).
36. Medicherla S, Ma JY, Mangadu R, Jiang Y, Zhao JJ, Almirez R, Kerr I, Stebbins EG, O'Young G, Kapoun AM, Luedtke G, Chakravarty S, Dugar S, Genant HK, Protter AA. A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J. Pharmacol. Exp. Ther., 318, 132-141 (2006)
37. Rioja I, Bush KA, Buckton JB, Dickson MC, Life PF. Joint cytokine quantification in two rodent arthritis models: kinetics of expression, correlation of mRNA and protein levels and response toprednisolone treatment. Clin. Exp. Immunol., 137, 65-73 (2004).
38. Marinova-Mutafchieva L, Williams RO, Mason LJ, Mauri C, Feldmann M, Maini RN. Dynamics of proinflammatory cytokine expression in the joints of mice with collagen-induced arthritis (CIA). Clin. Exp. Immunol., 107, 507-512 (1997).
39. Thornton S, Duwel LE, Boivin GP, Ma Y, Hirsch R. Association of the course of collagen-induced arthritis with distinct patterns of cytokine and chemokine messenger RNA expression. Arthritis Rheum., 42, 1109-1118 (1999).
40. Kagari T, Doi H, Shimozato T. The importance of IL-1 beta and TNF-alpha, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis. J. Immunol., 169, 1459-1466 (2002).
41. Tanaka S, Toki T, Akimoto T, Morishita K. Lipopolysaccharide accelerates collagen-induced arthritis in association with rapid and continuous production of inflammatory mediators and anti-type II collagen antibody. Microbiol. Immunol., 57, 445-454 (2013).
42. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res. Ther., 11, 224 (2009).
43. Yoshihara Y, Nakamura H, Obata K, Yamada H, Hayakawa T, Fujikawa K, Okada Y. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann. Rheum. Dis., 59, 455-461 (2000)
44. Tchetverikov I, Ronday HK, Van El B, Kiers GH, Verzijl N, TeKoppele JM, Huizinga TW, DeGroot J, Hanemaaijer R. MMP profile in paired serum and synovial fluid samples of patients with rheumatoid arthritis. Ann. Rheum. Dis., 63, 881-883 (2004).
45. Goldring SR. Bone and joint destruction in rheumatoid arthritis: what is really happening? J. Rheumatol. Suppl., 65, 44-48 (2002)
46. Williams RO. Collagen-induced arthritis in mice: A major role for tumor necrosis factor-alpha. Methods Mol. Biol., 361, 265-284 (2007).
47. Takagi N, Mihara M, Moriya Y, Nishimoto N, Yoshizaki K, Kishimoto T, Takeda Y, Ohsugi Y. Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum., 41, 2117-2121 (1998).
48. Williams RO, Marinova-Mutafchieva L, Feldmann M, Maini RN. Evaluation of TNF-alpha and IL-1 blockade in collagen-induced arthritis and comparison with combined anti-TNF-alpha/anti-CD4 therapy. J. Immunol., 165, 7240-7245 (2000).
49. Gamble C, McIntosh K, Scott R, Ho KH, Plevin R, Paul A. Inhibitory kappaB kinases as targets for pharmacological regulation. Br. J. Pharmacol., 165, 802-819 (2012)