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M40403

M-40403 is a superoxide dismutase mimetic, which is being evaluated  for the potential treatment of pain, dermatological disease, inflammation, as well as the treatment for the side effects associated with chemotherapy and radiation therapy. (source: IDrugs. 2005 Jan;8(1):67-76.)

This investigational small molecule mimics the action of a natural component of the cells, an enzyme called superoxide dismutase. Superoxide dismutase is thought to have a double pharmacologic effect during the early stages of tissue damage, first through the reduction of inflammation, and secondarily through the decreased rate of programmed cell death (apoptosis). As mucositis involves inflammation, the positive effect of the M40403 over this process is expected to have a beneficial effect in the condition. M40403 has shown efficacy in an animal model where oral mucositis was induced by acute irradiation. The compound has been evaluated in approximately 700 subjects in several Phase I and II clinical trials, and was shown to be safe and well-tolerated.

Current developer:    ActivBiotics Inc., Metaphore Pharmaceuticals, Inc..

 1: Wang C, Zhang X, Liu F, Paule MG, Slikker W Jr. Anesthetic-induced oxidative stress and potential protection. ScientificWorldJournal. 2010 Jul 20;10:1473-82. PubMed PMID: 20661539.

2: Lee H, Park W, Lim D. Synthesis and SOD activity of manganese complexes of substituted pyridino pentaaza macrocycles that contain axial auxiliary. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2421-4. Epub 2010 Mar 11. PubMed PMID: 20346657.

3: Thompson JS, Chu Y, Glass J, Tapp AA, Brown SA. The manganese superoxide dismutase mimetic, M40403, protects adult mice from lethal total body irradiation. Free Radic Res. 2010 May;44(5):529-40. PubMed PMID: 20298121.

4: Dennis KE, Aschner JL, Milatovic D, Schmidt JW, Aschner M, Kaplowitz MR, Zhang Y, Fike CD. NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L596-607. Epub 2009 Jul 10. PubMed PMID: 19592458; PubMed Central PMCID: PMC2770786.

5: Jaulmes A, Sansilvestri-Morel P, Rolland-Valognes G, Bernhardt F, Gaertner R, Lockhart BP, Cordi A, Wierzbicki M, Rupin A, Verbeuren TJ. Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells. Thromb Res. 2009 Sep;124(4):439-46. Epub 2009 Jun 21. PubMed PMID: 19540572.

6: Fike CD, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner JL. Reactive oxygen species from NADPH oxidase contribute to altered pulmonary vascular responses in piglets with chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2008 Nov;295(5):L881-8. Epub 2008 Aug 29. PubMed PMID: 18757525; PubMed Central PMCID: PMC2584882.

7: Xu Y, Liu B, Zweier JL, He G. Formation of hydrogen peroxide and reduction of peroxynitrite via dismutation of superoxide at reperfusion enhances myocardial blood flow and oxygen consumption in postischemic mouse heart. J Pharmacol Exp Ther. 2008 Nov;327(2):402-10. Epub 2008 Aug 6. PubMed PMID: 18685120; PubMed Central PMCID: PMC2615247.

8: Murphy CK, Fey EG, Watkins BA, Wong V, Rothstein D, Sonis ST. Efficacy of superoxide dismutase mimetic M40403 in attenuating radiation-induced oral mucositis in hamsters. Clin Cancer Res. 2008 Jul 1;14(13):4292-7. PubMed PMID: 18594012.

9: Maroz A, Kelso GF, Smith RA, Ware DC, Anderson RF. Pulse radiolysis investigation on the mechanism of the catalytic action of Mn(II)-pentaazamacrocycle compounds as superoxide dismutase mimetics. J Phys Chem A. 2008 Jun 5;112(22):4929-35. Epub 2008 May 13. PubMed PMID: 18473451.

10: Kondapaneni M, McGregor JR, Salvemini D, Laubach VE, Samlowski WE. Inducible nitric oxide synthase (iNOS) is not required for IL-2-induced hypotension and vascular leak syndrome in mice. J Immunother. 2008 May;31(4):325-33. PubMed PMID: 18391763.

11: Munroe W, Kingsley C, Durazo A, Gralla EB, Imlay JA, Srinivasan C, Valentine JS. Only one of a wide assortment of manganese-containing SOD mimicking compounds rescues the slow aerobic growth phenotypes of both Escherichia coli and Saccharomyces cerevisiae strains lacking superoxide dismutase enzymes. J Inorg Biochem. 2007 Nov;101(11-12):1875-82. Epub 2007 Jul 16. PubMed PMID: 17723242.

12: Cuzzocrea S, Mazzon E, di Paola R, Genovese T, Muià C, Caputi AP, Salvemini D. Synergistic interaction between methotrexate and a superoxide dismutase mimetic: pharmacologic and potential clinical significance. Arthritis Rheum. 2005 Dec;52(12):3755-60. PubMed PMID: 16320326.

13: Masini E, Bani D, Vannacci A, Pierpaoli S, Mannaioni PF, Comhair SA, Xu W, Muscoli C, Erzurum SC, Salvemini D. Reduction of antigen-induced respiratory abnormalities and airway inflammation in sensitized guinea pigs by a superoxide dismutase mimetic. Free Radic Biol Med. 2005 Aug 15;39(4):520-31. PubMed PMID: 16043023.

14: Cuzzocrea S, Mazzon E, Paola RD, Genovese T, Muià C, Caputi AP, Salvemini D. Effects of combination M40403 and dexamethasone therapy on joint disease in a rat model of collagen-induced arthritis. Arthritis Rheum. 2005 Jun;52(6):1929-40. PubMed PMID: 15934059.

15: Di Paola R, Mazzon E, Rotondo F, Dattola F, Britti D, De Majo M, Genovese T, Cuzzocrea S. Reduced development of experimental periodontitis by treatment with M40403, a superoxide dismutase mimetic. Eur J Pharmacol. 2005 Jun 1;516(2):151-7. PubMed PMID: 15921679.

16: Ndengele MM, Muscoli C, Wang ZQ, Doyle TM, Matuschak GM, Salvemini D. Superoxide potentiates NF-kappaB activation and modulates endotoxin-induced cytokine production in alveolar macrophages. Shock. 2005 Feb;23(2):186-93. PubMed PMID: 15665736.

17: Di Napoli M, Papa F. M-40403 Metaphore Pharmaceuticals. IDrugs. 2005 Jan;8(1):67-76. Review. PubMed PMID: 15650944.

18: Nicotera TM, Ding D, McFadden SL, Salvemini D, Salvi R. Paraquat-induced hair cell damage and protection with the superoxide dismutase mimetic m40403. Audiol Neurootol. 2004 Nov-Dec;9(6):353-62. Epub 2004 Oct 1. PubMed PMID: 15467288.

19: Muscoli C, Mollace V, Wheatley J, Masini E, Ndengele M, Wang ZQ, Salvemini D. Superoxide-mediated nitration of spinal manganese superoxide dismutase: a novel pathway in N-methyl-D-aspartate-mediated hyperalgesia. Pain. 2004 Sep;111(1-2):96-103. PubMed PMID: 15327813.

20: Di Filippo C, Cuzzocrea S, Marfella R, Fabbroni V, Scollo G, Berrino L, Giugliano D, Rossi F, D'Amico M. M40403 prevents myocardial injury induced by acute hyperglycaemia in perfused rat heart. Eur J Pharmacol. 2004 Aug 16;497(1):65-74. PubMed PMID: 15321736.

21: Rupin A, Paysant J, Sansilvestri-Morel P, Lembrez N, Lacoste JM, Cordi A, Verbeuren TJ. Role of NADPH oxidase-mediated superoxide production in the regulation of E-selectin expression by endothelial cells subjected to anoxia/reoxygenation. Cardiovasc Res. 2004 Aug 1;63(2):323-30. PubMed PMID: 15249190.

22: Cuzzocrea S, Pisano B, Dugo L, Ianaro A, Ndengele M, Salvemini D. Superoxide-related signaling cascade mediates nuclear factor-kappaB activation in acute inflammation. Antioxid Redox Signal. 2004 Aug;6(4):699-704. PubMed PMID: 15242550.

23: Wang C, Anastasio N, Popov V, Leday A, Johnson KM. Blockade of N-methyl-D-aspartate receptors by phencyclidine causes the loss of corticostriatal neurons. Neuroscience. 2004;125(2):473-83. PubMed PMID: 15062989.

24: Wang ZQ, Porreca F, Cuzzocrea S, Galen K, Lightfoot R, Masini E, Muscoli C, Mollace V, Ndengele M, Ischiropoulos H, Salvemini D. A newly identified role for superoxide in inflammatory pain. J Pharmacol Exp Ther. 2004 Jun;309(3):869-78. Epub 2004 Feb 26. PubMed PMID: 14988418.

25: Cuzzocrea S, Mazzon E, Dugo L, Di Paola R, Caputi AP, Salvemini D. Superoxide: a key player in hypertension. FASEB J. 2004 Jan;18(1):94-101. PubMed PMID: 14718390.

26: Ali BH. Agents ameliorating or augmenting experimental gentamicin nephrotoxicity: some recent research. Food Chem Toxicol. 2003 Nov;41(11):1447-52. Review. PubMed PMID: 12962996.

27: Arbiser JL. Role of manganese superoxide dismutase in cancer. Nat Med. 2003 Sep;9(9):1103; author reply 1103. PubMed PMID: 12949512.

28: Jiang F, Guo Y, Salvemini D, Dusting GJ. Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein(E)-deficient mice. Br J Pharmacol. 2003 Jul;139(6):1127-34. PubMed PMID: 12871831; PubMed Central PMCID: PMC1573947.

29: Weber DS, Griendling KK. The yin/yang of superoxide dismutase mimetics: potential cardiovascular therapies? Br J Pharmacol. 2003 Jul;139(6):1059-60. Review. PubMed PMID: 12871823; PubMed Central PMCID: PMC1573946.

30: Shimizu K, Rajapakse N, Horiguchi T, Payne RM, Busija DW. Neuroprotection against hypoxia-ischemia in neonatal rat brain by novel superoxide dismutase mimetics. Neurosci Lett. 2003 Jul 31;346(1-2):41-4. PubMed PMID: 12850543.

31: Sosman JA, Mier JW. Biological drug duo delivers one-two tumor punch. Nat Med. 2003 Jun;9(6):649-50. PubMed PMID: 12778160.

32: Marzocca C, Vannacci A, Cuzzocrea S, Salvemini D, Mannaioni PF, Masini E. Effects of the SOD mimetic, M40403, on prostaglandin production in an in vivo model of ischemia and reperfusion in rat heart. Inflamm Res. 2003 Apr;52 Suppl 1:S23-4. PubMed PMID: 12755394.

33: Samlowski WE, Petersen R, Cuzzocrea S, Macarthur H, Burton D, McGregor JR, Salvemini D. A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects. Nat Med. 2003 Jun;9(6):750-5. Epub 2003 May 5. PubMed PMID: 12730689.

34: Fries DM, Paxinou E, Themistocleous M, Swanberg E, Griendling KK, Salvemini D, Slot JW, Heijnen HF, Hazen SL, Ischiropoulos H. Expression of inducible nitric-oxide synthase and intracellular protein tyrosine nitration in vascular smooth muscle cells: role of reactive oxygen species. J Biol Chem. 2003 Jun 20;278(25):22901-7. Epub 2003 Apr 10. PubMed PMID: 12690103.

35: McFadden SL, Ding D, Salvemini D, Salvi RJ. M40403, a superoxide dismutase mimetic, protects cochlear hair cells from gentamicin, but not cisplatin toxicity. Toxicol Appl Pharmacol. 2003 Jan 1;186(1):46-54. PubMed PMID: 12583992.

36: Wang C, McInnis J, West JB, Bao J, Anastasio N, Guidry JA, Ye Y, Salvemini D, Johnson KM. Blockade of phencyclidine-induced cortical apoptosis and deficits in prepulse inhibition by M40403, a superoxide dismutase mimetic. J Pharmacol Exp Ther. 2003 Jan;304(1):266-71. PubMed PMID: 12490600.

37: Papaccio G, Nicoletti F, Pisanti FA, Galdieri M, Bendtzen K. An imidazoline compound completely counteracts interleukin-1[beta] toxic effects to rat pancreatic islet [beta] cells. Mol Med. 2002 Sep;8(9):536-45. PubMed PMID: 12456992; PubMed Central PMCID: PMC2040020.

38: Salvemini D, Muscoli C, Riley DP, Cuzzocrea S. Superoxide dismutase mimetics. Pulm Pharmacol Ther. 2002;15(5):439-47. Review. PubMed PMID: 12406666.

39: Cuzzocrea S, Mazzon E, Dugo L, Serraino I, Di Paola R, Britti D, De Sarro A, Pierpaoli S, Caputi A, Masini E, Salvemini D. A role for superoxide in gentamicin-mediated nephropathy in rats. Eur J Pharmacol. 2002 Aug 16;450(1):67-76. PubMed PMID: 12176111.

40: Salvemini D, Cuzzocrea S. Superoxide, superoxide dismutase and ischemic injury. Curr Opin Investig Drugs. 2002 Jun;3(6):886-95. Review. PubMed PMID: 12137408.

41: Salvemini D, Riley DP, Cuzzocrea S. SOD mimetics are coming of age. Nat Rev Drug Discov. 2002 May;1(5):367-74. Review. PubMed PMID: 12120412.

42: Masini E, Cuzzocrea S, Mazzon E, Marzocca C, Mannaioni PF, Salvemini D. Protective effects of M40403, a selective superoxide dismutase mimetic, in myocardial ischaemia and reperfusion injury in vivo. Br J Pharmacol. 2002 Jul;136(6):905-17. Erratum in: Br J Pharmacol. 2002 Dec;137(8):1387. PubMed PMID: 12110615; PubMed Central PMCID: PMC1573411.

43: Lysiak JJ, Nguyen QA, Turner TT. Peptide and nonpeptide reactive oxygen scavengers provide partial rescue of the testis after torsion. J Androl. 2002 May-Jun;23(3):400-9. PubMed PMID: 12002442.

44: McInnis J, Wang C, Anastasio N, Hultman M, Ye Y, Salvemini D, Johnson KM. The role of superoxide and nuclear factor-kappaB signaling in N-methyl-D-aspartate-induced necrosis and apoptosis. J Pharmacol Exp Ther. 2002 May;301(2):478-87. PubMed PMID: 11961046.

45: Salvemini D, Mazzon E, Dugo L, Serraino I, De Sarro A, Caputi AP, Cuzzocrea S. Amelioration of joint disease in a rat model of collagen-induced arthritis by M40403, a superoxide dismutase mimetic. Arthritis Rheum. 2001 Dec;44(12):2909-21. PubMed PMID: 11762952.

46: Cuzzocrea S, Mazzon E, Dugo L, Caputi AP, Riley DP, Salvemini D. Protective effects of M40403, a superoxide dismutase mimetic, in a rodent model of colitis. Eur J Pharmacol. 2001 Nov 30;432(1):79-89. PubMed PMID: 11734191.

47: Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Lund DD, Salvemini D, Yorek MA. Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Br J Pharmacol. 2001 Sep;134(1):21-9. PubMed PMID: 11522593; PubMed Central PMCID: PMC1572916.

48: Aston K, Rath N, Naik A, Slomczynska U, Schall OF, Riley DP. Computer-aided design (CAD) of Mn(II) complexes: superoxide dismutase mimetics with catalytic activity exceeding the native enzyme. Inorg Chem. 2001 Apr 9;40(8):1779-89. PubMed PMID: 11312732.

49: Salvemini D, Mazzon E, Dugo L, Riley DP, Serraino I, Caputi AP, Cuzzocrea S. Pharmacological manipulation of the inflammatory cascade by the superoxide dismutase mimetic, M40403. Br J Pharmacol. 2001 Feb;132(4):815-27. PubMed PMID: 11181422; PubMed Central PMCID: PMC1572614.

50: Cuzzocrea S, Mazzon E, Dugo L, Caputi AP, Aston K, Riley DP, Salvemini D. Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion. Br J Pharmacol. 2001 Jan;132(1):19-29. PubMed PMID: 11156557; PubMed Central PMCID: PMC1572533.

51: Salvemini D, Riley DP. Nonpeptidyl mimetics of superoxide dismutase in clinical therapies for diseases. Cell Mol Life Sci. 2000 Oct;57(11):1489-92. PubMed PMID: 11092442.

52: Macarthur H, Westfall TC, Riley DP, Misko TP, Salvemini D. Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9753-8. PubMed PMID: 10944234; PubMed Central PMCID: PMC16937.

53: Strauss E. Possible new anti-inflammatory agent. Science. 1999 Oct 8;286(5438):209-10. PubMed PMID: 10577184.

54: Salvemini D, Wang ZQ, Zweier JL, Samouilov A, Macarthur H, Misko TP, Currie MG, Cuzzocrea S, Sikorski JA, Riley DP. A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats. Science. 1999 Oct 8;286(5438):304-6. PubMed PMID: 10514375.