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Imisopasem manganese

Description of Imisopasem manganese (M40403): Imisopasem manganese (formerly as know as M40403)  is a stable non-peptidyl mimetic of MnSOD that crosses cell membranes and is effective in reducing experimental inflammation. Recent studuies found that M40403 was effective in reducing TBI-induced tissue destruction and had potential as a new radioprotective agent.  M40403 may offer a novel therapeutic approach for the management of various cardiovascular diseases where these radicals have been postulated to play a role.

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

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.

 1: 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.

2: 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.

3: 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.

4: 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.

5: 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.

6: 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.

7: 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.

8: 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.

9: 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.

10: 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.

11: 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.

12: 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.

13: 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.

14: 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.

15: 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.

16: 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.