MedKoo product information:

Doramapimod

Description of Doramapimod: Doramapimod (BIRB 796) is a member of the N-pyrazole-N'-naphthly urea class of p38MAPK inhibitors, which binds to the kinase with both slow association and dissociation rates. BIRB-796 has entered clinical trials for the treatment of autoimmune diseases.

Current developer:    Boehringer Ingelheim (Originator)  

BIRB796 inhibits the stress-activated protein kinases p38alpha and p38beta and is undergoing clinical trials for the treatment of inflammatory diseases.   However, research data showed that no clinical efficacy (primary end point, clinical remission; secondary end point, clinical response; Inflammatory Bowel Disease Questionnaire; Crohn's Disease Endoscopic Index of Severity) was seen for BIRB 796 in comparison with placebo. A significant, dose-dependent decrease of C-reactive protein level was observed transiently after BIRB 796 after 1 week with a return to baseline level over time. The incidence of adverse events was comparable between all treatment groups, with the exception of a mild increase of transaminase levels that was seen more frequently in the BIRB 796 groups. Geographic center effects were observed with Russian centers producing distinctly higher remission and response rates and lower adverse event rates than in other countries in both placebo and active treatment groups. CONCLUSIONS: There was no evidence for clinical efficacy of BIRB 796 in CD. A remarkable difference in the course of CD exists between Russia and non-Russian centers. (source: Clin Gastroenterol Hepatol. 2006 Mar;4(3):325-34. or http://www.ncbi.nlm.nih.gov/pubmed/16527696).

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2: Joos H, Albrecht W, Laufer S, Brenner RE. Differential effects of p38MAP kinase inhibitors on the expression of inflammation-associated genes in primary, interleukin-1beta-stimulated human chondrocytes. Br J Pharmacol. 2010 Jul;160(5):1252-62. PubMed PMID: 20590617.

3: Page TH, Brown A, Timms EM, Foxwell BM, Ray KP. p38 inhibitors suppress cytokine production in RA synovial membranes: Does variable inhibition of IL-6 production limit effectiveness in vivo? Arthritis Rheum. 2010 Jun 29. [Epub ahead of print] PubMed PMID: 20589681.

4: Namboodiri HV, Bukhtiyarova M, Ramcharan J, Karpusas M, Lee Y, Springman EB. Analysis of imatinib and sorafenib binding to p38alpha compared with c-Abl and b-Raf provides structural insights for understanding the selectivity of inhibitors targeting the DFG-out form of protein kinases. Biochemistry. 2010 May 4;49(17):3611-8. PubMed PMID: 20337484.

5: Chopra P, Kulkarni O, Gupta S, Bajpai M, Kanoje V, Banerjee M, Bansal V, Visaga S, Chatterjee M, Chaira T, Shirumalla RK, Verma AK, Dastidar SG, Sharma G, Ray A. Pharmacological profile of AW-814141, a novel, potent, selective and orally active inhibitor of p38 MAP kinase. Int Immunopharmacol. 2010 Apr;10(4):467-73. Epub 2010 Jan 20. PubMed PMID: 20093202.

6: Turpeinen T, Nieminen R, Moilanen E, Korhonen R. Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. J Pharmacol Exp Ther. 2010 Apr;333(1):310-8. Epub 2010 Jan 20. PubMed PMID: 20089808.

7: Tecle H, Feru F, Liu H, Kuhn C, Rennie G, Morris M, Shao J, Cheng AC, Gikunju D, Miret J, Coli R, Xi SH, Clugston SL, Low S, Kazmirski S, Ding YH, Cao Q, Johnson TL, Deshmukh GD, DiNitto JP, Wu JC, English JM. The design, synthesis and potential utility of fluorescence probes that target DFG-out conformation of p38alpha for high throughput screening binding assay. Chem Biol Drug Des. 2009 Dec;74(6):547-59. Epub 2009 Oct 20. PubMed PMID: 19843080.

8: Engstrom L, Pinzon-Ortiz MC, Li Y, Chen SC, Kinsley D, Nelissen R, Fine JS, Mihara K, Manfra D. Characterization of a murine keyhole limpet hemocyanin (KLH)-delayed-type hypersensitivity (DTH) model: role for p38 kinase. Int Immunopharmacol. 2009 Sep;9(10):1218-27. Epub 2009 Jul 16. PubMed PMID: 19616132.

9: Han S, Mistry A, Chang JS, Cunningham D, Griffor M, Bonnette PC, Wang H, Chrunyk BA, Aspnes GE, Walker DP, Brosius AD, Buckbinder L. Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design. J Biol Chem. 2009 May 8;284(19):13193-201. Epub 2009 Feb 25. PubMed PMID: 19244237; PubMed Central PMCID: PMC2676051.

10: Genovese MC. Inhibition of p38: has the fat lady sung? Arthritis Rheum. 2009 Feb;60(2):317-20. PubMed PMID: 19180514.

11: Klevernic IV, Morton S, Davis RJ, Cohen P. Phosphorylation of Ewing's sarcoma protein (EWS) and EWS-Fli1 in response to DNA damage. Biochem J. 2009 Mar 15;418(3):625-34. PubMed PMID: 19076070.

12: Gruenbaum LM, Schwartz R, Woska JR Jr, DeLeon RP, Peet GW, Warren TC, Capolino A, Mara L, Morelock MM, Shrutkowski A, Jones JW, Pargellis CA. Inhibition of pro-inflammatory cytokine production by the dual p38/JNK2 inhibitor BIRB796 correlates with the inhibition of p38 signaling. Biochem Pharmacol. 2009 Feb 1;77(3):422-32. Epub 2008 Nov 5. PubMed PMID: 19027720.

13: Angell RM, Angell TD, Bamborough P, Bamford MJ, Chung CW, Cockerill SG, Flack SS, Jones KL, Laine DI, Longstaff T, Ludbrook S, Pearson R, Smith KJ, Smee PA, Somers DO, Walker AL. Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4433-7. Epub 2008 Jun 12. PubMed PMID: 18602262.

14: Bagley MC, Davis T, Dix MC, Murziani PG, Rokicki MJ, Kipling D. Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38(MAPK) inhibitor RO3201195 for study in Werner syndrome cells. Bioorg Med Chem Lett. 2008 Jul 1;18(13):3745-8. Epub 2008 May 16. PubMed PMID: 18539026.

15: Cho SJ, Sun Y. Visual exploration of structure-activity relationship using maximum common framework. J Comput Aided Mol Des. 2008 Aug;22(8):571-8. Epub 2008 Mar 13. PubMed PMID: 18338222.

16: Torvinen M, Campwala H, Kilty I. The role of IFN-gamma in regulation of IFN-gamma-inducible protein 10 (IP-10) expression in lung epithelial cell and peripheral blood mononuclear cell co-cultures. Respir Res. 2007 Nov 8;8:80. PubMed PMID: 17996064; PubMed Central PMCID: PMC2174934.

17: Maekawa T, Ashihara E, Kimura S. The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias. Int J Clin Oncol. 2007 Oct;12(5):327-40. Epub 2007 Oct 22. Review. PubMed PMID: 17929114.

18: Moss N, Breitfelder S, Betageri R, Cirillo PF, Fadra T, Hickey ER, Kirrane T, Kroe RR, Madwed J, Nelson RM, Pargellis CA, Qian KC, Regan J, Swinamer A, Torcellini C. New modifications to the area of pyrazole-naphthyl urea based p38 MAP kinase inhibitors that bind to the adenine/ATP site. Bioorg Med Chem Lett. 2007 Aug 1;17(15):4242-7. Epub 2007 May 18. PubMed PMID: 17560108.

19: Soverini S, Iacobucci I, Baccarani M, Martinelli G. Targeted therapy and the T315I mutation in Philadelphia-positive leukemias. Haematologica. 2007 Apr;92(4):437-9. PubMed PMID: 17488653.

20: Bagley MC, Davis T, Dix MC, Widdowson CS, Kipling D. Microwave-assisted synthesis of N-pyrazole ureas and the p38alpha inhibitor BIRB 796 for study into accelerated cell ageing. Org Biomol Chem. 2006 Nov 21;4(22):4158-64. PubMed PMID: 17312972.

21: Park JK, Fischer R, Dechend R, Shagdarsuren E, Gapeljuk A, Wellner M, Meiners S, Gratze P, Al-Saadi N, Feldt S, Fiebeler A, Madwed JB, Schirdewan A, Haller H, Luft FC, Muller DN. p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. Hypertension. 2007 Mar;49(3):481-9. Epub 2007 Jan 15. PubMed PMID: 17224470.

22: Yasui H, Hideshima T, Ikeda H, Jin J, Ocio EM, Kiziltepe T, Okawa Y, Vallet S, Podar K, Ishitsuka K, Richardson PG, Pargellis C, Moss N, Raje N, Anderson KC. BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth. Br J Haematol. 2007 Feb;136(3):414-23. Epub 2006 Dec 14. PubMed PMID: 17173546.

23: Kimura S, Ashihara E, Maekawa T. New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Curr Pharm Biotechnol. 2006 Oct;7(5):371-9. Review. PubMed PMID: 17076652.

24: Zaman GJ, van der Lee MM, Kok JJ, Nelissen RL, Loomans EE. Enzyme fragment complementation binding assay for p38alpha mitogen-activated protein kinase to study the binding kinetics of enzyme inhibitors. Assay Drug Dev Technol. 2006 Aug;4(4):411-20. PubMed PMID: 16945014.

25: Danese S, Semeraro S, Armuzzi A, Papa A, Gasbarrini A. Biological therapies for inflammatory bowel disease: research drives clinics. Mini Rev Med Chem. 2006 Jul;6(7):771-84. Review. PubMed PMID: 16842127.

26: Jia Y, Quinn CM, Gagnon AI, Talanian R. Homogeneous time-resolved fluorescence and its applications for kinase assays in drug discovery. Anal Biochem. 2006 Sep 15;356(2):273-81. Epub 2006 May 24. PubMed PMID: 16814737.

27: Schreiber S, Feagan B, D'Haens G, Colombel JF, Geboes K, Yurcov M, Isakov V, Golovenko O, Bernstein CN, Ludwig D, Winter T, Meier U, Yong C, Steffgen J; BIRB 796 Study Group. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006 Mar;4(3):325-34. PubMed PMID: 16527696.

28: Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem. 2005;12(25):2979-94. Review. PubMed PMID: 16378500.

29: O'Hare T, Druker BJ. BIRB-796 is not an effective ABL(T315I) inhibitor. Nat Biotechnol. 2005 Oct;23(10):1209-10; author reply 1210-1. PubMed PMID: 16211050.

30: Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK, Milanov ZV, Atteridge CE, Biggs WH 3rd, Edeen PT, Floyd M, Ford JM, Grotzfeld RM, Herrgard S, Insko DE, Mehta SA, Patel HK, Pao W, Sawyers CL, Varmus H, Zarrinkar PP, Lockhart DJ. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11011-6. Epub 2005 Jul 26. PubMed PMID: 16046538; PubMed Central PMCID: PMC1180625.

31: Dominguez C, Powers DA, Tamayo N. p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel. 2005 Jul;8(4):421-30. Review. PubMed PMID: 16022178.

32: Wilkens SJ, Janes J, Su AI. HierS: hierarchical scaffold clustering using topological chemical graphs. J Med Chem. 2005 May 5;48(9):3182-93. PubMed PMID: 15857124.

33: Kuma Y, Sabio G, Bain J, Shpiro N, Márquez R, Cuenda A. BIRB796 inhibits all p38 MAPK isoforms in vitro and in vivo. J Biol Chem. 2005 May 20;280(20):19472-9. Epub 2005 Mar 8. PubMed PMID: 15755732.

34: Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005 Mar;23(3):329-36. Epub 2005 Feb 13. PubMed PMID: 15711537.

35: Dumas J, Smith RA, Lowinger TB. Recent developments in the discovery of protein kinase inhibitors from the urea class. Curr Opin Drug Discov Devel. 2004 Sep;7(5):600-16. Review. PubMed PMID: 15503863.

36: Lukas SM, Kroe RR, Wildeson J, Peet GW, Frego L, Davidson W, Ingraham RH, Pargellis CA, Labadia ME, Werneburg BG. Catalysis and function of the p38 alpha.MK2a signaling complex. Biochemistry. 2004 Aug 10;43(31):9950-60. PubMed PMID: 15287722.

37: van den Blink B, Branger J, Weijer S, Gupta A, van Deventer SJ, Peppelenbosch MP, van der Poll T. P38 mitogen activated protein kinase is involved in the downregulation of granulocyte CXC chemokine receptors 1 and 2 during human endotoxemia. J Clin Immunol. 2004 Jan;24(1):37-41. PubMed PMID: 14997032.

38: Regan J, Capolino A, Cirillo PF, Gilmore T, Graham AG, Hickey E, Kroe RR, Madwed J, Moriak M, Nelson R, Pargellis CA, Swinamer A, Torcellini C, Tsang M, Moss N. Structure-activity relationships of the p38alpha MAP kinase inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796). J Med Chem. 2003 Oct 23;46(22):4676-86. PubMed PMID: 14561087.

39: Regan J, Pargellis CA, Cirillo PF, Gilmore T, Hickey ER, Peet GW, Proto A, Swinamer A, Moss N. The kinetics of binding to p38MAP kinase by analogues of BIRB 796. Bioorg Med Chem Lett. 2003 Sep 15;13(18):3101-4. PubMed PMID: 12941343.

40: Evans R. Anti-arthritic agents--SMi conference: trapping cytokines. 28-29 April 2003, London, UK. IDrugs. 2003 Jun;6(6):548-51. PubMed PMID: 12861982.

41: Branger J, van den Blink B, Weijer S, Gupta A, van Deventer SJ, Hack CE, Peppelenbosch MP, van der Poll T. Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. Blood. 2003 Jun 1;101(11):4446-8. Epub 2003 Feb 6. PubMed PMID: 12576315.

42: Regan J, Breitfelder S, Cirillo P, Gilmore T, Graham AG, Hickey E, Klaus B, Madwed J, Moriak M, Moss N, Pargellis C, Pav S, Proto A, Swinamer A, Tong L, Torcellini C. Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate. J Med Chem. 2002 Jul 4;45(14):2994-3008. PubMed PMID: 12086485.

43: Branger J, van den Blink B, Weijer S, Madwed J, Bos CL, Gupta A, Yong CL, Polmar SH, Olszyna DP, Hack CE, van Deventer SJ, Peppelenbosch MP, van der Poll T. Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol. 2002 Apr 15;168(8):4070-7. PubMed PMID: 11937566.

44: Pargellis C, Tong L, Churchill L, Cirillo PF, Gilmore T, Graham AG, Grob PM, Hickey ER, Moss N, Pav S, Regan J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol. 2002 Apr;9(4):268-72. PubMed PMID: 11896401.