Small molecules with anti-inflammatory properties in clinical development

Pharmacology and Therapeutics

Volumn 157, Issue , 2016, Pages 163-187

  Hanke, Thomas ^a   Merk, Daniel ^a   Steinhilber, Dieter ^a   Geisslinger, Gerd ^a   Schubert Zsilavecz, Manfred ^a  

^a GOETHE UNIVERSITY   (Germany)

Author keywords

Chronic obstructive pulmonary disease; Clinical trials; Inflammatory bowel diseases; Multiple sclerosis; Psoriasis; Rheumatoid arthritis

Indexed keywords

ANTIINFLAMMATORY AGENT; ARACHIDONIC ACID; CATHEPSIN S INHIBITOR; CHEMOKINE; CHEMOKINE RECEPTOR; CHEMOKINE RECEPTOR CCR1 ANTAGONIST; CHEMOKINE RECEPTOR CCR2 ANTAGONIST; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; CHEMOKINE RECEPTOR CCR9 ANTAGONIST; CHEMOKINE RECEPTOR CXCR2 ANTAGONIST; DIHYDROOROTATE DEHYDROGENASE INHIBITOR; GLUCOCORTICOID RECEPTOR ANTAGONIST; INTEGRIN RECEPTOR ANTAGONIST; LEUKOCYTE ELASTASE INHIBITOR; LIGAND; LYASE INHIBITOR; MATRIX METALLOPROTEINASE INHIBITOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PHOSPHODIESTERASE INHIBITOR; PHOSPHOLIPID; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN INHIBITOR; PURINERGIC P2X RECEPTOR ANTAGONIST; SELECTIVE GLUCOCORTICOID RECEPTOR AGONIST; SPHINGOSINE 1 PHOSPHATE RECEPTOR MODULATOR; STAT3 PROTEIN INHIBITOR; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ARTICLE; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL (TOPIC); HUMAN; INFLAMMATORY BOWEL DISEASE; MULTIPLE SCLEROSIS; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PSORIASIS; RHEUMATOID ARTHRITIS; ANIMAL; ARTHRITIS, RHEUMATOID; INFLAMMATORY BOWEL DISEASES; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ARTHRITIS, RHEUMATOID; HUMANS; INFLAMMATORY BOWEL DISEASES; MULTIPLE SCLEROSIS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 84952638969     PISSN: 01637258     EISSN: 1879016X     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2015.11.011     Document Type: Review

References (175)

1. C. Agen, R. Danesi, C. Blandizzi, M. Costa, B. Stacchini, P. Favini, and et al. Macrolide antibiotics as antiinflammatory agents: roxithromycin in an unexpected role Agents Actions 38 1993 85 90
2. R.K. Albert, J. Connett, W.C. Bailey, R. Casaburi, J.A.D. Cooper, G.J. Criner, and et al. Azithromycin for prevention of exacerbations of COPD N Engl J Med 365 8 2011 689 698
3. R.E. Alten, C. Zerbini, S. Jeka, F. Irazoque, F. Khatib, P. Emery, and et al. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy Ann Rheum Dis 69 2 2010 364 367
4. M. Amat, C.F. Benjamim, L.M. Williams, N. Prats, E. Terricabras, J. Beleta, and et al. Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo Br J Pharmacol 149 6 2006 666 675
5. Anacor Pharmaceuticals Pipeline Crisaborole online available: http://www.anacor.com/an2728.php 2015 (last checked: 21.08.2015)
6. G.D. Anderson, K.L. Keys, P.A. De Ciechi, and J.L. Masferrer Combination therapies that inhibit cyclooxygenase-2 and leukotriene synthesis prevent disease in murine collagen induced arthritis Inflamm Res 58 2 2009 109 117
7. D.L. Auci, K. Mangano, D. Destiche, S.K. White, Y. Huang, D. Boyle, and et al. Oral treatment with HE3286 ameliorates disease in rodent models of rheumatoid arthritis Int J Mol Med 25 2010 625 633
8. D.L. Auci, C.L. Reading, and J.M. Frincke 7-Hydroxy androstene steroids and a novel synthetic analogue with reduced side effects as a potential agent to treat autoimmune diseases Autoimmun Rev 8 5 2009 369 372
9. G. Bain, C.D. King, K. Schaab, M. Rewolinski, V. Norris, C. Ambery, and et al. Pharmacodynamics, pharmacokinetics and safety of GSK2190915, a novel oral anti-inflammatory 5-lipoxygenase-activating protein inhibitor Br J Clin Pharmacol 75 3 2013 779 790
10. P.J. Barnes Defective antioxidant gene regulation in COPD: a case for broccoli Am J Respir Crit Care Med 178 6 2008 552 554
11. P.J. Barnes New anti-inflammatory targets for chronic obstructive pulmonary disease Nat Rev Drug Discov 12 7 2013 543 559
12. D.C. Baumgart, and W.J. Sandborn Crohn's disease Lancet 380 9853 2012 1590 1605
13. J.A. Bernstein, N. Liu, B.A. Knorr, S.S. Smugar, W.D. Hanley, T.F. Reiss, and et al. MK-0633, a potent 5-lipoxygenase inhibitor, in chronic obstructive pulmonary disease Respir Med 105 3 2011 392 401
14. S.J. Bickston, K.R. Snider, and M.R. Kappus Tetomilast: new promise for phosphodiesterase-4 inhibitors? Expert Opin Investig Drugs 21 12 2012 1845 1849
15. L. Boring, J. Gosling, S.W. Chensue, S.L. Kunkel, R.V. Farese, H.E. Broxmeyer, and et al. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice J Clin Invest 100 10 1997 2552 2561
16. L. Boring, J. Gosling, M. Cleary, and I.F. Charo Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis Nature 394 6696 1998 894 897
17. A. Boutten, D. Goven, E. Artaud-Macari, J. Boczkowski, and M. Bonay NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease Trends Mol Med 17 7 2011 363 371
18. F.C. Breedveld, M.H. Weisman, A.F. Kavanaugh, S.B. Cohen, K. Pavelka, R. van Vollenhoven, and et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment Arthritis Rheum 54 1 2006 26 37
19. P. Brossard, H. Derendorf, J. Xu, H. Maatouk, A. Halabi, and J. Dingemanse Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P 1 receptor modulator, in the first-in-human study Br J Clin Pharmacol 76 6 2013 888 896
20. J. Calkwood, B. Cree, H. Crayton, D. Kantor, B. Steingo, L. Barbato, and et al. Impact of a switch to fingolimod versus staying on glatiramer acetate or beta interferons on patient- and physician-reported outcomes in relapsing multiple sclerosis: post hoc analyses of the EPOC trial BMC Neurol 14 1 2014 220
21. F. Celotti, and S. Laufer Anti-inflammatory drugs: new multitarget compounds to face an old problem. The dual inhibition concept Pharmacol Res 43 5 2001 429 436
22. Z. Chen, Y. Wu, Y. Liu, S. Yang, Y. Chen, and L. Lai Discovery of dual target inhibitors against cyclooxygenases and leukotriene A4 hydrolyase J Med Chem 54 10 2011 3650 3660
23. M. Clementina, and S. Giuseppe A2A receptor ligands: past, present and future trends Curr Top Med Chem 10 2010 902 922
24. S.B. Cohen, T.-T. Cheng, V. Chindalore, N. Damjanov, R. Burgos-Vargas, P. Delora, and et al. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis Arthritis Rheum 60 2 2009 335 344
25. A.J. Coles, A. Cox, E. Le Page, J. Jones, S.A. Trip, J. Deans, and et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy J Neurol 253 1 2006 98 108
26. A.J. Coles, E. Fox, A. Vladic, S.K. Gazda, V. Brinar, K.W. Selmaj, and et al. Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes Lancet Neurol 10 4 2011 338 348
27. D. Conrad, A. Wang, R. Pieters, F. Nicoletti, K. Mangano, A.M. van Heeckeren, and et al. HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression J Inflamm 7 2010 52
28. M.G. Cosio, M. Saetta, and A. Agusti Immunologic aspects of chronic obstructive pulmonary disease N Engl J Med 360 23 2009 2445 2454
29. R. Dahl, I. Titlestad, A. Lindqvist, P. Wielders, H. Wray, M. Wang, and et al. Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial Pulm Pharmacol Ther 25 2 2012 169 177
30. D.J. Dairaghi, P. Zhang, Y. Wang, L.C. Seitz, D.A. Johnson, S. Miao, and et al. Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCX354 in healthy human subjects: implications for selection of clinical dose Clin Pharmacol Ther 89 5 2011 726 734
31. N. Damjanov, R.S. Kauffman, and G.T. Spencer-Green Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies Arthritis Rheum 60 5 2009 1232 1241
32. M. David, L. Akerman, M. Ziv, M. Kadurina, D. Gospodinov, F. Pavlotsky, and et al. Treatment of plaque-type psoriasis with oral CF101: data from an exploratory randomized phase 2 clinical trial J Eur Acad Dermatol Venereol 26 3 2012 361 367
33. W.I. de Boer, H. Yao, and I. Rahman Future therapeutic treatment of COPD: struggle between oxidants and cytokines Int J Chron Obstruct Pulmon Dis 2 2007 205 228
34. F. Díaz-González, R.H.E. Alten, W.G. Bensen, J.P. Brown, J.T. Sibley, M. Dougados, and et al. Clinical trial of a leucotriene B4 receptor antagonist, BIIL 284, in patients with rheumatoid arthritis Ann Rheum Dis 66 5 2007 628 632
35. C.A. Dinarello Anti-inflammatory agents: present and future Cell 140 6 2010 935 950
36. I. Dotan, D. Rachmilewitz, S. Schreiber, R. Eliakim, C.J. van der Woude, A. Kornbluth, and et al. A randomised placebo-controlled multicentre trial of intravenous semapimod HCl for moderate to severe Crohn's disease Gut 59 6 2010 760 766
37. Y. Ducharme, M. Blouin, C. Brideau, A. Châteauneuf, Y. Gareau, E.L. Grimm, and et al. The discovery of setileuton, a potent and selective 5-lipoxygenase inhibitor ACS Med Chem Lett 1 4 2010 170 174
38. Y. Edmonds, S. Milstien, and S. Spiegel Development of small-molecule inhibitors of sphingosine-1-phosphate signaling Pharmacol Ther 132 3 2011 352 360
39. S. Fiorucci, R. Meli, M. Bucci, and G. Cirino Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy? Biochem Pharmacol 62 2001 1433 1438
40. L.R. Fitzpatrick, L. Deml, C. Hofmann, J.S. Small, M. Groeppel, S. Hamm, and et al. 4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease† Inflamm Bowel Dis 16 10 2010 1763 1777
41. R. Fleischmann Novel small-molecular therapeutics for rheumatoid arthritis Curr Opin Rheumatol 24 3 2012 335 341
42. R.M. Fleischmann, N.S. Damjanov, A.J. Kivitz, A. Legedza, T. Hoock, and N. Kinnman A randomized, double-blind, placebo-controlled, twelve-week, dose-ranging study of decernotinib, an oral selective jak-3 inhibitor, as monotherapy in patients with active rheumatoid arthritis Arthritis Rheum 67 2 2015 334 343
43. M. Forrest, S.-Y. Sun, R. Hajdu, J. Bergstrom, D. Card, G. Doherty, and et al. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes J Pharmacol Exp Ther 309 2 2004 758 768
44. R. Frank, and R. Hargreaves Clinical biomarkers in drug discovery and development Nat Rev Drug Discov 2 7 2003 566 580
45. C.D. Funk Prostaglandins and leukotrienes: advances in eicosanoid biology Science 294 5548 2001 1871 1875
46. M.C. Genovese, S.B. Cohen, D. Wofsy, M.E. Weinblatt, G.S. Firestein, E. Brahn, and et al. A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis J Rheumatol 38 5 2011 846 854
47. M.C. Genovese, A. Kavanaugh, M.E. Weinblatt, C. Peterfy, J. DiCarlo, M.L. White, and et al. An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents Arthritis Rheum 63 2 2011 337 345
48. P. Gergely, B. Nuesslein-Hildesheim, D. Guerini, V. Brinkmann, M. Traebert, C. Bruns, and et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate Br J Pharmacol 167 5 2012 1035 1047
49. D.M. Gerlag, S. Hollis, M. Layton, J. Vencovský, Z. Szekanecz, M. Braddock, and et al. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate Arthritis Rheum 62 11 2010 3154 3160
50. K. Ghoreschi, A. Laurence, and J.J. O'Shea Selectivity and therapeutic inhibition of kinases: to be or not to be? Nat Immunol 10 4 2009 356 360
51. R.A. Grove, S. Shackelford, S. Sopper, S. Pirruccello, J. Horrigan, E. Havrdova, and et al. Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis Eur J Neurol 20 7 2013 1032 1042
52. S. Gupta, R.K. Singh, S. Dastidar, and A. Ray Cysteine cathepsin S as an immunomodulatory target: present and future trends Expert Opin Ther Targets 12 3 2008 291 299
53. J.Z. Haeggström, and C.D. Funk Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease Chem Rev 111 10 2011 5866 5898
54. D. Hammaker, and G.S. Firestein "Go upstream, young man": lessons learned from the p38 saga Ann Rheum Dis 69 Suppl. 1 2010 i77 i82
55. T. Hanke, F. Dehm, S. Liening, S.-D. Popella, J. Maczewsky, M. Pillong, and et al. Aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 inhibitors with improved potency and efficiency in vivo J Med Chem 56 22 2013 9031 9044
56. J.J. Haringman, T.J.M. Smeets, P. Reinders-Blankert, and P.P. Tak Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis Ann Rheum Dis 65 3 2006 294 300
57. G. Haskó, J. Linden, B. Cronstein, and P. Pacher Adenosine receptors: therapeutic aspects for inflammatory and immune diseases Nat Rev Drug Discov 7 9 2008 759 770
58. E. Havrdova, D. Horakova, and I. Kovarova Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use Ther Adv Neurol Disord 8 1 2015 31 45
59. C. He, Y. Wu, Y. Lai, Z. Cai, Y. Liu, and L. Lai Dynamic eicosanoid responses upon different inhibitor and combination treatments on the arachidonic acid metabolic network Mol BioSyst 8 5 2012 1585 1594
60. K. Herrlinger, M. Diculescu, K. Fellermann, H. Hartmann, S. Howaldt, R. Nikolov, and et al. Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study J Crohns Colitis 7 8 2013 636 643
61. O. Holz, S. Khalilieh, A. Ludwig-Sengpiel, H. Watz, P. Stryszak, P. Soni, and et al. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects Eur Respir J 35 3 2010 564 570
62. R. Horuk Chemokine receptor antagonists: overcoming developmental hurdles Nat Rev Drug Discov 8 1 2008 23 33
63. J. Hu, P.E. van den Steen, Q.-X.A. Sang, and G. Opdenakker Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases Nat Rev Drug Discov 6 6 2007 480 498
64. T. Huynh The multiple sclerosis market Nat Rev Drug Discov 9 10 2010 759 760
65. D.B. Jack One hundred years of aspirin Lancet 350 9075 1997 437 439
66. C.C. Kaiser, D.K. Shukla, G.T. Stebbins, D.D. Skias, D.R. Jeffery, D. Stefoski, and et al. A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis J Neuroimmunol 211 1-2 2009 124 130
67. J. Kalliomäki, N. Attal, B. Jonzon, F.W. Bach, K. Huizar, S. Ratcliffe, and et al. A randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia Pain 154 5 2013 761 767
68. W.J. Karpus, and K.J. Kennedy MIP-1alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomyelitis as well as Th1/Th2 lymphocyte differentiation J Leukoc Biol 62 1997 681 687
69. C.T. Keith, A.A. Borisy, and B.R. Stockwell Multicomponent therapeutics for networked systems Nat Rev Drug Discov 4 1 2005 71 78
70. H.A. Kerstjens, L. Bjermer, L. Eriksson, K. Dahlström, and J. Vestbo Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients Respir Med 104 9 2010 1297 1303
71. S. Keshav, T. Vaňásek, Y. Niv, R. Petryka, S. Howaldt, M. Bafutto, and et al. A randomized controlled trial of the efficacy and safety of CCX282-B, an orally-administered blocker of chemokine receptor CCR9, for patients with Crohn's disease PLoS One 8 3 2013 e60094
72. E.C. Keystone, P.C. Taylor, E. Drescher, D.E. Schlichting, S.D. Beattie, P.-Y. Berclaz, and et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate Ann Rheum Dis 74 2 2015 333 340
73. E.C. Keystone, M.M. Wang, M. Layton, S. Hollis, and I.B. McInnes Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine Ann Rheum Dis 71 10 2012 1630 1635
74. J. Killestein, R.A. Rudick, and C.H. Polman Oral treatment for multiple sclerosis Lancet Neurol 10 11 2011 1026 1034
75. T. Kirchner, B. Aparicio, D.C. Argentieri, C.Y. Lau, and D.M. Ritchie Effects of tepoxalin, a dual inhibitor of cyclooxygenase/5-lipoxygenase, on events associated with NSAID-induced gastrointestinal inflammation Prostaglandins Leukot Essent Fatty Acids 56 1997 417 423
76. A. Koeberle, U. Siemoneit, U. Bühring, H. Northoff, S. Laufer, W. Albrecht, and et al. Licofelone suppresses prostaglandin E2 formation by interference with the inducible microsomal prostaglandin E2 synthase-1 J Pharmacol Exp Ther 326 3 2008 975 982
77. T. Komiya, K. Sato, H. Shioya, Y. Inagaki, H. Hagiya, R. Kozaki, and et al. Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis Clin Exp Immunol 171 1 2013 54 62
78. K. Kragballe, P.C.M. van de Kerkhof, and K.B. Gordon Unmet needs in the treatment of psoriasis Eur J Dermatol 24 5 2014 523 532
79. M.S. Krathen, A.B. Gottlieb, and P.J. Mease Pharmacologic immunomodulation and cutaneous malignancy in rheumatoid arthritis, psoriasis, and psoriatic arthritis J Rheumatol 37 11 2010 2205 2215
80. A. Kumar, and J.D. Saba Lyase to live by: sphingosine phosphate lyase as a therapeutic target Expert Opin Ther Targets 13 8 2009 1013 1025
81. P. Kuna, M. Jenkins, C.D. O'Brien, and W.A. Fahy AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD Respir Med 106 4 2012 531 539
82. V. Lajevardi, Z. Hallaji, S. Daklan, R. Abedini, A. Goodarzi, and M. Abdolreza The efficacy of methotrexate plus pioglitazone vs. methotrexate alone in the management of patients with plaque-type psoriasis: a single-blinded randomized controlled trial Int J Dermatol 54 1 2015 95 101
83. A.L. Lazaar, L.E. Sweeney, A.J. MacDonald, N.E. Alexis, C. Chen, and R. Tal-Singer SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans Br J Clin Pharmacol 72 2 2011 282 293
84. A. Lee-Dutra, D.K. Wiener, and S. Sun Cathepsin S inhibitors: 2004-2010 Expert Opin Ther Pat 21 3 2011 311 337
85. J.S. Levine, and R. Burakoff Extraintestinal manifestations of inflammatory bowel disease Gastroenterol Hepatol 7 2011 235 241
86. Lilly & Incyte Lilly and Incyte Announce Positive Top-Line Results From Phase 3 Trial of Baricitinib in Moderate to Severe Rheumatoid Arthritis online available: https://investor.lilly.com/releasedetail.cfm?releaseid=886732 2014 (last checked: 21.08.2015)
87. T.M. Lindstrom, and W.H. Robinson A multitude of kinases - which are the best targets in treating rheumatoid arthritis? Rheum Dis Clin N Am 36 2 2010 367 383
88. D.S. Lorrain, G. Bain, L.D. Correa, C. Chapman, A.R. Broadhead, A.M. Santini, and et al. Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation Eur J Pharmacol 640 1-3 2010 211 218
89. J. Lötsch, and G. Geisslinger Low-dose drug combinations along molecular pathways could maximize therapeutic effectiveness while minimizing collateral adverse effects Drug Discov Today 16 23-24 2011 1001 1006
90. F. Luessi, V. Siffrin, and F. Zipp Neurodegeneration in multiple sclerosis: novel treatment strategies Expert Rev Neurother 12 9 2012 1061 1076 (quiz 1077)
91. A.-H. Maghzi, A. Minagar, and E. Waubant Neuroprotection in multiple sclerosis: a therapeutic approach CNS Drugs 27 10 2013 799 815
92. I.B. McInnes, and G. Schett The pathogenesis of rheumatoid arthritis N Engl J Med 365 23 2011 2205 2219
93. R. Medzhitov Origin and physiological roles of inflammation Nature 454 7203 2008 428 435
94. I. Melnikova Psoriasis market Nat Rev Drug Discov 8 10 2009 767 768
95. X. Meng, P.S. Chin, R. Hashmonay, M. Zahur Islam, and G. Cutter Effect of switching from intramuscular interferon β-1a to oral fingolimod on time to relapse in patients with relapsing-remitting multiple sclerosis enrolled in a 1-year extension of TRANSFORMS Contemp Clin Trials 41C 2014 69 74
96. Merck Merck Reaches Mutual Agreement with Ono Pharmaceutical to Terminate the License Agreement on Ceralifimod (ONO-4641) online available: http://www.merckgroup.com/en/media/extNewsDetail.html?newsId=3509C61F2069D5B2C1257CF9004DD829&newsType=1 2014 (last checked: 21.08.2015)
97. A.E. Miller, P. O'Connor, J.S. Wolinsky, C. Confavreux, L. Kappos, T.P. Olsson, and et al. Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis Mult Scler 18 11 2012 1625 1632
98. D.H. Miller, T. Weber, R. Grove, C. Wardell, J. Horrigan, O. Graff, and et al. Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial Lancet Neurol 11 2 2012 131 139
99. R. Mittal, S. Malhotra, P. Pandhi, I. Kaur, and S. Dogra Efficacy and safety of combination Acitretin and Pioglitazone therapy in patients with moderate to severe chronic plaque-type psoriasis: a randomized, double-blind, placebo-controlled clinical trial Arch Dermatol 145 4 2009 387 393
100. K. Miyoshi, M. Takaishi, K. Nakajima, M. Ikeda, T. Kanda, M. Tarutani, and et al. Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor J Invest Dermatol 131 1 2010 108 117
101. N.A. Molodecky, I.S. Soon, D.M. Rabi, W.A. Ghali, M. Ferris, G. Chernoff, and et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review Gastroenterology 142 1 2012 46 54 (e42; quiz e30)
102. R. Morphy, C. Kay, and Z. Rankovic From magic bullets to designed multiple ligands Drug Discov Today 9 15 2004 641 651
103. R.B. Moss, S.J. Mistry, M.W. Konstan, J.M. Pilewski, E. Kerem, R. Tal-Singer, and et al. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis J Cyst Fibros 12 3 2013 241 248
104. R.E. Mrak, and G.E. Landreth PPARgamma, neuroinflammation, and disease J Neuroinflammation 1 1 2004 5
105. K. Muramoto, M. Goto, Y. Inoue, N. Ishii, K. Chiba, Y. Kuboi, and et al. E6201, a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration J Pharmacol Exp Ther 335 1 2010 23 31
106. M.E. Muroski, M.D. Roycik, R.G. Newcomer, P.E. van den Steen, G. Opdenakker, H.R. Monroe, and et al. Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis Curr Pharm Biotechnol 9 2008 34 46
107. P.M. Murphy, M. Baggiolini, I.F. Charo, C.A. Hébert, R. Horuk, K. Matsushima, and et al. International union of pharmacology. XXII. Nomenclature for chemokine receptors Pharmacol Rev 52 2000 145 176
108. P. Nair, M. Gaga, E. Zervas, K. Alagha, F.E. Hargreave, P.M. O'Byrne, and et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial Clin Exp Allergy 42 7 2012 1097 1103
109. F.O. Nestle, D.H. Kaplan, and J. Barker Psoriasis N Engl J Med 361 5 2009 496 509
110. R. Nicholas, P. Giannetti, A. Alsanousi, T. Friede, and P.A. Muraro Development of oral immunomodulatory agents in the management of multiple sclerosis Drug Des Devel Ther 5 2011 255 274
111. C.L. Nickerson-Nutter, and E.D. Medvedeff The effect of leukotriene synthesis inhibitors in models of acute and chronic inflammation Arthritis Rheum 39 1996 515 521
112. B.J. Nickoloff Cracking the cytokine code in psoriasis Nat Med 13 3 2007 242 244
113. H. Obinata, and T. Hla Sphingosine 1-phosphate in coagulation and inflammation Semin Immunopathol 34 1 2012 73 91
114. P. O'Connor, J.S. Wolinsky, C. Confavreux, G. Comi, L. Kappos, T.P. Olsson, and et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis N Engl J Med 365 14 2011 1293 1303
115. H. Ogata, M. Takeya, T. Yoshimura, K. Takagi, and K. Takahashi The role of monocyte chemoattractant protein-1 (MCP-1) in the pathogenesis of collagen-induced arthritis in rats J Pathol 182 1 1997 106 114
116. T. Ohta, K. Iijima, M. Miyamoto, I. Nakahara, H. Tanaka, M. Ohtsuji, and et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth Cancer Res 68 5 2008 1303 1309
117. I. Ordás, L. Eckmann, M. Talamini, D.C. Baumgart, and W.J. Sandborn Ulcerative colitis Lancet 380 9853 2012 1606 1619
118. K. Papp, A. Menter, B. Strober, R. Langley, M. Buonanno, R. Wolk, and et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study Br J Dermatol 167 3 2012 668 677
119. J.-S. Park, S.-K. Kwok, M.-A. Lim, E.-K. Kim, J.-G. Ryu, S.-M. Kim, and et al. STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis Arthritis Rheum 66 4 2014 918 929
120. H.A. Pershadsingh, M.T. Heneka, R. Saini, N.M. Amin, D.J. Broeske, and D.L. Feinstein Effect of pioglitazone treatment in a patient with secondary multiple sclerosis J Neuroinflammation 1 1 2004 3
121. K.A. Phillips, S. van Bebber, and A.M. Issa Diagnostics and biomarker development: priming the pipeline Nat Rev Drug Discov 5 6 2006 463 469
122. A. Prat, and O. Stüve Firategrast - natalizumab in a pill? Lancet Neurol 11 2 2012 120 121
123. K.D. Rainsford Anti-inflammatory drugs in the 21st century Subcell Biochem 42 2007 3 27
124. J. Rask-Madsen, K. Bukhave, L.S. Laursen, and K. Lauritsen 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease Agents and actions, Spec No, C37-46 1992
125. S.I. Rennard, P.M.A. Calverley, U.M. Goehring, D. Bredenbröker, and F.J. Martinez Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD Respir Res 12 2011 18
126. S.I. Rennard, D.C. Dale, J.F. Donohue, F. Kanniess, H. Magnussen, E.R. Sutherland, and et al. CXCR2 antagonist MK-7123 - a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease Am J Respir Crit Care Med 191 2015 1001 1011
127. K.C. Reuter, C.R. Grunwitz, B.M. Kaminski, D. Steinhilber, H.H. Radeke, and J. Stein Selective glucocorticoid receptor agonists for the treatment of inflammatory bowel disease: studies in mice with acute trinitrobenzene sulfonic acid colitis J Pharmacol Exp Ther 341 1 2012 68 80
128. W.J. Sandborn, S. Ghosh, J. Panes, I. Vranic, C. Su, S. Rousell, and et al. Tofacitinib, an oral janus kinase inhibitor, in active ulcerative colitis N Engl J Med 367 7 2012 616 624
129. M.G. Sanna, J. Liao, E. Jo, C. Alfonso, M.-Y. Ahn, M.S. Peterson, and et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate J Biol Chem 279 14 2004 13839 13848
130. S. Sano, K.S. Chan, S. Carbajal, J. Clifford, M. Peavey, K. Kiguchi, and et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model Nat Med 11 1 2004 43 49
131. H. Schäcke, A. Schottelius, W.-D. Döcke, P. Strehlke, S. Jaroch, N. Schmees, and et al. Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects Proc Natl Acad Sci U S A 101 1 2004 227 232
132. M. Seiberling, T. Kamtchoua, P. Stryszak, X. Ma, R.B. Langdon, and S. Khalilieh Humoral immunity and delayed-type hypersensitivity in healthy subjects treated for 30 days with MK-7123, a selective CXCR2 antagonist Int Immunopharmacol 17 2 2013 178 183
133. K. Selmaj, David K.B. Li, H.-P. Hartung, B. Hemmer, L. Kappos, M.S. Freedman, and et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study Lancet Neurol 12 8 2013 756 767
134. N. Shafiq, S. Malhotra, P. Pandhi, M. Gupta, B. Kumar, and K. Sandhu Pilot trial: pioglitazone versus placebo in patients with plaque psoriasis (the P6) Int J Dermatol 44 4 2005 328 333
135. D. Shahin, E.E. Toraby, H. Abdel-Malek, V. Boshra, A.Z. Elsamanoudy, and D. Shaheen Effect of peroxisome proliferator-activated receptor gamma agonist (pioglitazone) and methotrexate on disease activity in rheumatoid arthritis (experimental and clinical study) Clin Med Insights Arthritis Musculoskelet Disord 4 2011 1 10
136. D.K. Shukla, C.C. Kaiser, G.T. Stebbins, and D.L. Feinstein Effects of pioglitazone on diffusion tensor imaging indices in multiple sclerosis patients Neurosci Lett 472 3 2010 153 156
137. S. Siebert, A. Tsoukas, J. Robertson, and I. McInnes Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases Pharmacol Rev 67 2 2015 280 309
138. M.H. Silverman, V. Strand, D. Markovits, M. Nahir, T. Reitblat, Y. Molad, and et al. Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial J Rheumatol 35 2008 41 48
139. A. Singh, V. Misra, R.K. Thimmulappa, H. Lee, S. Ames, M.O. Hoque, and et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer PLoS Med 3 10 2006 e420
140. S.J. Smith Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes Mol Pharmacol 66 6 2004 1679 1689
141. J.S. Smolen, R. Landewé, F.C. Breedveld, M. Buch, G. Burmester, M. Dougados, and et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update Ann Rheum Dis 73 3 2014 492 509
142. J.S. Smolen, R. Landewé, F.C. Breedveld, M. Dougados, P. Emery, C. Gaujoux-Viala, and et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs Ann Rheum Dis 69 6 2010 964 975
143. N. Snell, M. Foster, and J. Vestbo Efficacy and safety of AZD1981, a CRTH2 receptor antagonist, in patients with moderate to severe COPD Respir Med 107 11 2013 1722 1730
144. S. Spiegel, and S. Milstien The outs and the ins of sphingosine-1-phosphate in immunity Nat Rev Immunol 11 6 2011 403 415
145. K.J. Stebbins, A.R. Broadhead, C. Chapman, L. Correa, A.M. Santini, P. Prodanovich, and et al. The 5-lipoxygenase-activating protein (FLAP) inhibitor GSK2190915, reduces cigarette smoke-induced pulmonary inflammation in the mouse Am J Respir Crit Care Med 183 2011 (A3091-A3091)
146. K.J. Stebbins, J.F. Evans, and D.S. Lorrain DP2 receptor antagonists: novel therapeutic target for COPD Mol Cell Pharmacol 2 2010 89 96
147. N.S. Stock, G. Bain, J. Zunic, Y. Li, J. Ziff, J. Roppe, and et al. 5-Lipoxygenase-activating protein (FLAP) inhibitors. Part 4: development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor J Med Chem 54 23 2011 8013 8029
148. T.C. Stock, B.J. Bloom, N. Wei, S. Ishaq, W. Park, X. Wang, and et al. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate J Rheumatol 39 4 2012 720 727
149. J.G. Stoll, and U. Yasothan Rheumatoid arthritis market Nat Rev Drug Discov 8 9 2009 693 694
150. K. Sugimoto Role of STAT3 in inflammatory bowel disease World J Gastroenterol 14 33 2008 5110
151. P.P. Tak, A. Balanescu, V. Tseluyko, S. Bojin, E. Drescher, D. Dairaghi, and et al. Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial Ann Rheum Dis 72 3 2013 337 344
152. T. Takenouchi, K. Sekiyama, A. Sekigawa, M. Fujita, M. Waragai, S. Sugama, and et al. P2X7 receptor signaling pathway as a therapeutic target for neurodegenerative diseases Arch Immunol Ther Exp 58 2 2010 91 96
153. P.C. Taylor, A.M. Peters, E. Paleolog, P.T. Chapman, M.J. Elliott, R. McCloskey, and et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis Arthritis Rheum 43 1 2000 38 47
154. M.M. Thabet, and T.W.J. Huizinga Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis Curr Opin Investig Drugs 7 2006 1014 1019
155. T. Thalhamer, M.A. McGrath, and M.M. Harnett MAPKs and their relevance to arthritis and inflammation Rheumatology 47 4 2007 409 414
156. S. Thomas, and D.C. Baumgart Targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis Inflammopharmacology 20 1 2012 1 18
157. K. Tizaoui, A. Naouali, W. Kaabachi, A. Hamzaoui, and K. Hamzaoui Association of Toll like receptor Asp299Gly with rheumatoid arthritis risk: a systematic review of case-control studies and meta-analysis Pathol Res Pract 211 3 2015 219 225
158. L. Ulloa The vagus nerve and the nicotinic anti-inflammatory pathway Nat Rev Drug Discov 4 8 2005 673 684
159. A. Vaclavkova, S. Chimenti, P. Arenberger, P. Holló, P.-G. Sator, M. Burcklen, and et al. Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial Lancet 384 9959 2014 2036 2045
160. S. Vandevyver, L. Dejager, J. Tuckermann, and C. Libert New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation Endocrinology 154 3 2013 993 1007
161. A. Viola, and A.D. Luster Chemokines and their receptors: drug targets in immunity and inflammation Annu Rev Pharmacol Toxicol 48 2008 171 197
162. C. Vogelmeier, T.O. Aquino, C.D. O'Brien, J. Perrett, and K.A. Gunawardena A randomised, placebo-controlled, dose-finding study of AZD9668, an oral inhibitor of neutrophil elastase, in patients with chronic obstructive pulmonary disease treated with tiotropium COPD 9 2 2012 111 120
163. M.J. Walters, Y. Wang, N. Lai, T. Baumgart, B.N. Zhao, D.J. Dairaghi, and et al. Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease J Pharmacol Exp Ther 335 1 2010 61 69
164. H. Wang, M. Yu, M. Ochani, C.A. Amella, M. Tanovic, S. Susarla, and et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation Nature 421 6921 2003 384 388
165. S.J. Webb, T.E. Geoghegan, R.A. Prough, and K.K. Michael Miller The biological actions of dehydroepiandrosterone involves multiple receptors Drug Metab Rev 38 1-2 2006 89 116
166. M.E. Weinblatt, A. Kavanaugh, R. Burgos-Vargas, A.H. Dikranian, G. Medrano-Ramirez, J.L. Morales-Torres, and et al. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial Arthritis Rheum 58 11 2008 3309 3318
167. M.E. Weinblatt, A. Kavanaugh, M.C. Genovese, D.A. Jones, T.K. Musser, E.B. Grossbard, and et al. Effects of fostamatinib (R788), an oral spleen tyrosine kinase inhibitor, on health-related quality of life in patients with active rheumatoid arthritis: analyses of patient-reported outcomes from a randomized, double-blind, placebo-controlled trial J Rheumatol 40 2013 369 378
168. M.E. Weinblatt, A. Kavanaugh, M.C. Genovese, T.K. Musser, E.B. Grossbard, and D.B. Magilavy An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis N Engl J Med 363 14 2010 1303 1312
169. M.E. Weinblatt, J.M. Kremer, J.S. Coblyn, S. Helfgott, A.L. Maier, G. Petrillo, and et al. Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis J Rheumatol 19 1992 1537 1541
170. J.J.M. Wiener, S. Sun, and R.L. Thurmond Recent advances in the design of cathepsin S inhibitors Curr Top Med Chem 10 2010 717 732
171. T. Wisniewski, E. Bayne, J. Flanagan, Q. Shao, R. Wnek, S. Matheravidathu, and et al. Assessment of chemokine receptor function on monocytes in whole blood: in vitro and ex vivo evaluations of a CCR2 antagonist J Immunol Methods 352 1-2 2010 101 110
172. C. Wolf, J. Sidhu, C. Otoul, D.L. Morris, J. Cnops, J. Taubel, and et al. Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study PLoS One 8 3 2013 e58438
173. U. Yasothan, and S. Kar Therapies for COPD Nat Rev Drug Discov 7 4 2008 285 286
174. H. Yu, D. Pardoll, and R. Jove STATs in cancer inflammation and immunity: a leading role for STAT3 Nat Rev Cancer 9 11 2009 798 809
175. D. Zeeuw, T. de Akizawa, P. Audhya, G.L. Bakris, M. Chin, H. Christ-Schmidt, and et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease N Engl J Med 369 26 2013 2492 2503