Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease

Expert Opinion on Investigational Drugs

Volumn 24, Issue 3, 2015, Pages 383-392

  Norman, Peter ^a  

^a NORMAN CONSULTING   (United Kingdom)

Author keywords

Chronic obstructive pulmonary disease; Inflammation; Inhaled drug; P38 inhibitor

Indexed keywords

ACUMAPIMOD; AZD 7624; GSK 610677; LOSMAPIMOD; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PF 03715455; PH 797804; RV 568; UNCLASSIFIED DRUG; MITOGEN ACTIVATED PROTEIN KINASE P38; PROTEIN KINASE INHIBITOR;

CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL EVALUATION; DRUG DESIGN; DRUG EFFICACY; HUMAN; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; VALIDATION STUDY; ANIMAL; ANTAGONISTS AND INHIBITORS; DISEASE MODEL; DRUG DELIVERY SYSTEM; PATHOPHYSIOLOGY; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

ANIMALS; DISEASE MODELS, ANIMAL; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN KINASE INHIBITORS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 84923044041     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2015.1006358     Document Type: Review

References (78)

1. Lee JC, Young PR. Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. J Leukoc Biol 1996;59(2):152-7
2. Lee JC, Laydon JT, McDonnell PC, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 1994;372(6508):739-46. The identification of p38 kinase.
3. Wang XS, Diener K, Manthey CL, et al. Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase. J Biol Chem 1997;272(38):23668-74
4. O'Callaghan C, Fanning LJ, Barry OP. p38d MAPK: Emerging Roles of a Neglected Isoform. Int J Cell Biol 2014;2014:272689
5. Meng F, Wu G. Is p38g MAPK a metastasis-promoting gene or an oncogenic property-maintaining gene? Cell Cycle 2013;12(14):2329-30
6. Yang K, Liu Y, Liu Z, et al. p38g overexpression in gliomas and its role in proliferation and apoptosis. Sci Rep 2013;3:2089
7. Salituro FG, Germann UA, Wilson KP, et al. Inhibitors of p38 MAP kinase: therapeutic intervention in cytokinemediated diseases. Curr Med Chem 1999;6(9):807-23
8. Lee JC, Kumar S, Griswold DE, et al. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 2000;47:185-201
9. Fischer S, Koeberle SC, Laufer SA. p38alpha mitogen-activated protein kinase inhibitors, a patent review (2005-2011). Expert Opin Ther Pat 2011;21:1843-66
10. Global initiative for chronic Obstructive Lung Disease (GOLD 2014). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2014. Available from: www.goldcopd. org/uploads/users/files/ GOLD-Report-2014.pdf
11. Hanania NA, Donohue JF. Pharmacologic interventions in chronic obstructive pulmonary disease: bronchodilators. Proc Am Thorac Soc 2007;4(7):526-34
12. Norman P. New dual-acting bronchodilator treatments for COPD, muscarinic antagonists and b2 agonists in combination or combined into a single molecule. Expert Opin Investig Drugs 2013;22(12):1569-80
13. Barnes PJ. Inhaled corticosteroids in COPD: a controversy. Respiration 2010;80(2):89-95
14. Beghè B, Rabe KF, Fabbri LM. Phosphodiesterase-4 inhibitor therapy for lung diseases. Am J Respir Crit Care Med 2013;188(3):271-8
15. Antoniu SA. New therapeutic options in the management of COPD-focus on roflumilast. Int J Chron Obstruct Pulmon Dis 2011;6:147-55
16. Tamimi A, Serdarevic D, Hanania NA. The effects of cigarette smoke on airway inflammation in asthma and COPD: therapeutic implications. Respir Med 2012;106(3):319-28
17. Renda T, Baraldo S, Pelaia G, et al. Increased activation of p38 MAPK in COPD. Eur Respir J 2008;31(1):62-9
18. Gaffey K, Reynolds S, Plumb J, et al. Increased phosphorylated p38 mitogenactivated protein kinase in COPD lungs. Eur Respir J 2013;42(1):28-41
19. Armstrong J, Harbron C, Lea S, et al. Synergistic effects of p38 mitogenactivated protein kinase inhibition with a corticosteroid in alveolar macrophages from patients with chronic obstructive pulmonary disease. J Pharmacol Exp Ther 2011;338(3):732-40
20. Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol 2013;131(3):636-45
21. Schett G, Zwerina J, Firestein G. The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis 2008;67(7):909-16
22. Cohen SB, Cheng TT, Chindalore V, 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 2009;60(2):335-44
23. Genovese MC, Cohen SB, Wofsy D, et al. A 24-week, randomized, doubleblind, 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 2011;38(5):846-54
24. Genovese MC. Inhibition of p38: has the Fat Lady Sung? Arthritis Rheum 2009;60(2):317-20
25. Clark AR, Dean JL. The p38 MAPK Pathway in Rheumatoid Arthritis: a Sideways Look. Open Rheumatol J 2012;6:209-19
26. Malemud CJ. Dysfunctional immunemediated inflammation in rheumatoid arthritis dictates that development of anti-rheumatic disease drugs target multiple intracellular signaling pathways. Antiinflamm Antiallergy Agents Med Chem 2011;10(2):78-84
27. Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 2013;13(9):679-92
28. Marber MS, Rose B, Wang Y. The p38 mitogen-activated protein kinase pathway-a potential target for intervention in infarction, hypertrophy, and heart failure. J Mol Cell Cardiol 2011;51(4):485-90
29. Lin X, Wang M, Zhang J, Xu R. p38 MAPK: potential target of chronic pain. Curr Med Chem 2014;21(38):4405-18
30. Yong HY, Koh MS, Moon A. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs 2009;18(12):1893-905
31. Chiesi Farmaceutici S.P.A. Kinase Inhibitors. WO2013083606; 2013
32. Safety & Efficacy of BCT197A2201 in chronic obstructive pulmonary disease (copd) patients presenting with an exacerbation. Available from: https:// clinicaltrials.gov/ct2/show/NCT01332097
33. Novartis AG. 5-membered heterocyclebased p38 kinase inhibitors. US 8242117; 2012
34. Novartis AG. Use of a Pyrazole derivative in the treatment of acute exacerbations of chronic obstructive pulmonary disease. WO2013139809; 2013
35. Aston NM, Bamborough P, Buckton JB, et al. p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression. J Med Chem 2009;52(20):6257-69
36. Watz H, Barnacle H, Hartley B, Chan RA. Randomised, double-blind, placebo-controlled trial of the efficacy and safety of losmapimod in patients with chronic obstructive pulmonary disease. Lancet Respir Med 2014;2(1):63-72. A Phase II study in COPD patients.
37. Fisk M, Mohan D, Cheriyan J, et al. Evaluation of losmapimod in patients with chronic obstructive pulmonary disease (COPD) with systemic inflammation stratified using fibrinogen ('EVOLUTION'): rationale and protocol. Artery Res 2014;8(1):24-34
38. Lomas DA, Lipson DA, Miller BE, et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol 2012;52(3):416-24
39. Xing L, Devadas B, Devraj RV, et al. Discovery and characterization of atropisomer PH-797804, a p38 MAP kinase inhibitor, as a clinical drug candidate. ChemMedChem 2012;7(2):273-80
40. Hope HR, Anderson GD, Burnette BL, et al. Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation. J Pharmacol Exp Ther 2009;331(3):882-95
41. MacNee W, Allan RJ, Jones I, et al. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax 2013;68(8):738-45
42. Study to evaluate the efficacy and safety of PH-797804 for 12 weeks in adults with moderate to severe chronic obstructive pulmonary disease (COPD) taking salmeterol xinafoate/fluticasone propionate combination. Available from: https://clinicaltrials.gov/ct2/show/ NCT01321463
43. Fogel R, Shields K, Christensen J, et al. A phase II, randomised, placebo controlled trial of 12 weeks treatment with an oral p38 inhibitor in patients with COPD on a background of ICS/ LABA [abstract 186]. Annual Congress of the European Respiratory Society, Barcelona; 7-11 September 2013; 2013
44. Study to evaluate the efficacy and safety of ph-797804 for 12 weeks in adults with moderate to severe chronic obstructive pulmonary disease (copd) on a background of tiotropium bromide. Available from: https://clinicaltrials.gov/ ct2/show/NCT01543919
45. Tan E, Jones I, Tweedy S, et al. The novel oral p38 inhibitor, PH-797804, inhibits inhaled lipopolysaccharide (lps)-induced airway and systemic inflammatory markers. In healthy subjects ajrccm-conference, Denver; 13-18 May 2011; 2011. 183.1-MeetingAbstracts.A2554
46. Single dose lipopolysaccharide (lps) study in healthy volunteers. Available from: https://clinicaltrials.gov/ct2/show/ NCT01314885
47. Singh D, Smyth L, Borrill Z, et al. A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. J Clin Pharmacol 2010;50(1):94-100
48. Mayer RJ, Betts JC, Warnock LC, et al. Differential regulation of camp receptor protein (CRP) and fibrinogen gene expression by the p38 mitogen-activated protein (MAP) kinase inhibitor dilmapimod in blood samples obtained in a randomised, placebo controlled study in chronic obstructive pulmonary disease (COPD). Available from: www. atsjournals.org/doi/abs/10.1164/ajrccmconference. 2014.189.1-MeetingAbstracts. A4954
49. Barnes N, Pavord I, Maden C, et al. Evaluation of an oral p38 mitogen activated protein kinase (MAPK inhibitor) SB-681323 in COPD. Eur Respir J 2009;34(Suppl 53):648s
50. AstraZeneca AB. Pharmaceutical product comprising a p38 kinase inhibitor and a second active ingredient. WO-2010071583; 2010
51. AstraZeneca AB, AstraZeneca UK Ltd. Pyrazinone derivatives and their use in the treatment of lung diseases. WO-2009001132; 2009
52. To assess the safety, tolerability, and pharmacokinetics of azd7624 in healthy volunteers and copd patients. Available from: https://clinicaltrials.gov/ct2/show/ NCT01817855
53. A phase iia study to investigate the efficacy and safety of azd7624 in chronic obstructive pulmonary disease (COPD) patients while on maintenance therapy. Available from: https://clinicaltrials.gov/ ct2/show/NCT02238483
54. Millan DS, Bunnage ME, Burrows JL, et al. Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease. J Med Chem 2011;54(22):7797-814
55. Kilty I, Clarke N, Fairmain D, et al. PF-03715455: An inhaled p38 inhibitor for the treatment of chronic obstructive pulmonary disease P1764. Available from: www.ersnet.org/ learning-resources-player/ abstract-print-13/files/196.pdf
56. Russell V, Foster M, Spicer D, et al. The effects of pf03715455 and roflumilast on cellular and tissue inflammation [abstract A1504]. In an 11 day tobacco-smoke exposed mouse model Of COPD, abstracts of the American Thoracic Society, Philadelphia; 17-22 May 2013
57. An Evaluation Of PF-03715455 In Moderate To Severe Uncontrolled Asthma. Available from: https:// clinicaltrials.gov/ct2/show/NCT02219048
58. Johnson & Johnson, Centocor Ortho Biotech Inc. acquires respivert ltd., strengthens pulmonary focus acquisition bolsters pulmonary portfolio and capabilities, accessing promising pipeline of first-in-class compounds and renowned team of respiratory scientists, Press release, 1 June 2010
59. Charron C, Coates M, Ito K, et al. Superior effects Of RV568, a novel narrow spectrum kinase inhibitor, To BIRB796, A p38mapk inhibitor, on proinflammatory cytokine roduction. In macrophages, ajrccm-conference, Denver; 13-18 May 2011;2011. 183.1-MeetingAbstracts.A3088
60. Contoli C, Ito K, Papi A. Effects of rv568, a narrow spectrum kinase inhibitor, on hrv16 replication and cytokine production. In Airway epithelial cells obtained from COPD patients ajrccm-conference, Denver; 13-18 May 2011; 2011. 183.1-MeetingAbstracts.A2766
61. Knoblock J, Urban K, Jungck D, et al. Effects of rv568, a narrow spectrum kinase inhibitor, on pro-inflammatory cytokine production. In Smooth muscle cells obtained from COPD patients, ajrccm-conference, Denver; 13-18 May 2011;2011. 183.1-MeetingAbstracts.A3613
62. Ito K, Vuppusetty C, To M, Rapeport G. Effects of rv568, a narrow spectrum kinase inhibitor. On human rhinovirus replication and cytokine production, ajrccm-conference, Denver; 13-18 May 2011; 2011. 183.1-MeetingAbstracts.A2765
63. Contoli M, Ito K, Poletti D, et al. Novel narrow spectrum kinase inhibitors inhibit rhinovirus replication via enhancement of interferon expression in nasal epithelial cells of atopic and non-atopic patients. Eur Respir J 2011;p3495
64. Ito K, Vuppusetty C, To M. Effects of rv568, a narrow spectrum kinase inhibitor. On haemophillus influenzae infection to bronchial epithelial cells, ajrccm-conference, Denver; 13-18 May 2011; 2011. 183.1-MeetingAbstracts.A3359
65. Kizawa Y, Kimura G, Saito R, et al. Effects Of RV568, A narrow spectrum kinase inhibitor. on airway inflammation and hyperresponsiveness. In tobaccosmoke exposed mice, ajrccm-conference, Denver; 13-18 May 2011; 2011. 183.1-MeetingAbstracts.A3103
66. Langenbach S, Dousha L, Gulano RC, et al. Effects Of RV568, a narrow spectrum kinase inhibitor (NSKI), on influenza infection. In cigarette-smoke exposed mice, ajrccm-conference, Denver; 13-18 May 2011; 2011. 183.1-MeetingAbstracts.A3366
67. Charron C, Coates M, Ito K, et al. Superior effects of rv1088, a novel narrow spectrum kinase inhibitor, To BIRB796, A P38MAPK inhibitor, on pro-inflammatory cytokine production. In macrophages, ajrccm-conference, Denver; 13-18 May 2011; 2011. 183.1-MeetingAbstracts.A4538
68. Onions S. The discovery and profile of narrow spectrum kinase inhibitors as novel treatments for inflammatory pulmonary disease. 17th RSC/SCI medicinal chemistry symposium; Cambridge, 8-11 September 2013. The only discussion to date of Respivert's p38 strategy.
69. Respivert Ltd. p38 map kinase inhibitors. WO-2010038085; 2010
70. Respivert Ltd. 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy) napththalen-1-yl) ureas as p38 MAP kinase inhibitors. WO2010112936; 2013
71. RV568-Viral Challenge With RSV. Available from: https://clinicaltrials.gov/ ct2/show/NCT01230645
72. Vienna Challenge Chamber Study Using RV568 in Subjects With Allergic Rhinitis. Available from: https:// clinicaltrials.gov/ct2/show/NCT01230619
73. Cass L, Woodward K, Brindley C, et al. Tolerability and pharmacokinetic profile Of RV568, a narrow spectrum kinase inhibitor, following single and repeat inhaled dosing. In healthy volunteers, 10.1164/ajrccm-conference, Philadelphia; 17-22 May 2013; 2013. 187.1-MeetingAbstracts.A4117
74. Russell P, Cass L, Ito K, et al. Safety, pharmacokinetic and pharmacodynamic profile of RV568, a narrow spectrum kinase inhibitor, following repeat inhaled dosing in COPD patients. Eur Resp J 2013;42:1371
75. Ito K, Charron C, Cass L, et al. Pharmacodynamic analysis of rv568, a narrow spectrum kinase inhibitor, following single and repeat intranasal dosing. In healthy volunteers, 10.1164/ ajrccm-conference, Philadelphia; 17-22 May 2013; 2013. 187.1-MeetingAbstracts.A1494
76. An Effectiveness and safety study of inhaled jnj 49095397 (rv568) in patients with moderate to severe chronic obstructive pulmonary disease. Available from: https://clinicaltrials.gov/ct2/show/ NCT01867762
77. Marumo S, Hoshino Y, Kiyokawa H, et al. p38 mitogen-activated protein kinase determines the susceptibility to cigarette smoke-induced emphysema in mice. BMC Pulm Med 2014;14:79
78. Chung KF. p38 mitogen-activated protein kinase pathways in asthma and COPD. Chest 2011;139(6):1470-9