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Chemical Compound Review

Galardin     (2R)-N'-hydroxy-N-[(1S)-2- (1H-indol-3-yl)...

Synonyms: Ilomastat, Galardin MPI, CHEMBL19611, CS-610, BSPBio_001079, ...
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Disease relevance of Ilomastat


High impact information on Ilomastat

  • Growth activity was unlikely due to TIMP-2 inhibition of matrix metalloproteinases because ilomastat, a synthetic inhibitor of these enzymes, had no mesenchymal growth action [6].
  • The addition of MMP inhibitors (GM 6001 and TIMP-1) dramatically accelerated the accumulation of lipid during differentiation [7].
  • However, when plasminogen-deficient mice were treated with galardin, healing was completely arrested and wound closure was not seen during an observation period of 100 days, demonstrating that protease activity is essential for skin wound healing [8].
  • The expression of several matrix metalloproteases in keratinocytes migrating to cover the wound was strongly enhanced by galardin treatment [8].
  • Interestingly, the matrix metalloproteinase inhibitor GM6001 (ilomastat), which is currently in clinical development, was found to also target the neprilysin, aminopeptidase, and dipeptidylpeptidase clans of MPs [9].

Chemical compound and disease context of Ilomastat


Biological context of Ilomastat


Anatomical context of Ilomastat

  • In the present study, an MMP inhibitor, GM 6001, was administered to rats for various times after balloon injury of the carotid artery [17].
  • L1-dependent neurite outgrowth of cerebellar neurons was inhibited by GM 6001, suggesting that proteolytic processing of L1 by a metalloprotease is involved in neurite outgrowth [18].
  • TNF-alpha-stimulated wt microglia treated with the MMP inhibitor ilomastat also showed reduced neurotoxicity [19].
  • Impaired wound contraction (P < 0.01) was associated with a dramatic reduction of ASMA-positive myofibroblasts in granulation tissue of GM 6001 wounds [16].
  • GM 6001-treated wounds were minimally resurfaced with neoepithelium, despite unaltered keratinocyte proliferation in wound edges, whereas control wounds were completely covered with 3-7 cell layers of parakeratinized epithelium on post-wounding day 7 [16].

Associations of Ilomastat with other chemical compounds

  • PGE2-elicited chemokinesis of RNK-16 cells across a Matrigel model basement membrane, but not across a microfilter alone, was suppressed by the GM 6001 inhibitor of MMP activities [20].
  • The expansion was reduced significantly by the addition of either RU486 or Galardin, a broad-spectrum matrix metalloproteinase inhibitor [21].
  • Neurite outgrowth from cerebellar microexplants was inhibited in the presence of the metalloprotease inhibitor GM 6001 on substrate-coated NCAM, but not on poly-l-lysine [22].
  • Three inhibitors of angiogenesis, tamoxifen, ilomastat, and echistatin, were used to assess the efficiency of our ERCT to discriminate, in vitro, an angiostatic potential [23].
  • Pretreatment of these cells with either AG-1478 or GM-6001 reduced ANG II-stimulated DNA synthesis by approximately 50% [24].

Gene context of Ilomastat

  • A broad-spectrum metalloproteinase inhibitor, GM6001/Ilomastat, acted synergistically with Abeta to enhance neurotoxicity through a FasL-dependent mechanism [25].
  • EGF pathway inhibitors Galardin and AG1478 did not reduce BrdU incorporation in the monolayer, indicating that the EGF-receptor-mediated morphogenetic behavior is mainly due to cell migration rather than proliferation [26].
  • Furthermore, addition of galardin post-bombesin stimulation indicated that by 3 h sufficient accumulation of EGFR ligands had occurred to continue to induce transactivation despite an inhibition of MMP activity [27].
  • Galardin treatment also inhibited extracellular signal-regulated kinase (ERK) activation induced by bombesin or LPA, but not by EGF [27].
  • This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNF alpha processing and release and attenuate endotoxin-induced mortality [28].

Analytical, diagnostic and therapeutic context of Ilomastat

  • Inhibition of MMP activity resulted in a 97% decrease in the number of SMCs that migrated into the intima by 4 days after injury, and lesions growth was retarded by continuous treatment with GM 6001-treated rats was 0.035 +/- 0.008 mm2 compared with 0.095 +/- mm2 in the control group [17].
  • PURPOSE: To determine the long-term antiscarring effect of ilomastat treatment after experimental glaucoma filtration surgery (GFS) [29].
  • This inhibition correlated with a significant reduction in the number of capillaries with observable breaks in the basement membrane, as assessed by electron microscopy (0.27 +/- 0.27% in GM-6001-treated muscles compared with 3.72 +/- 0.65% in control stimulated muscles) [30].
  • Orthodontic tooth movement was inhibited by local delivery of Ilomastat, a general matrix metalloproteinase inhibitor, with the use of ethylene-vinyl-acetate (ELVAX) 40, a non-biodegradable, non-inflammatory sustained-release polymer [31].
  • The concentration of solubilized GM 6001 in wound fluid obtained from treated porcine wounds was 0.06 mg/ml (150 microM) as determined by high-performance liquid chromatography [32].


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  13. A functional overlap of plasminogen and MMPs regulates vascularization during placental development. Solberg, H., Rinkenberger, J., Danø, K., Werb, Z., Lund, L.R. Development (2003) [Pubmed]
  14. Involvement of 26-kDa cell-associated TNF-alpha in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor. Solorzano, C.C., Ksontini, R., Pruitt, J.H., Hess, P.J., Edwards, P.D., Kaibara, A., Abouhamze, A., Auffenberg, T., Galardy, R.E., Vauthey, J.N., Copeland, E.M., Edwards, C.K., Lauwers, G.Y., Clare-Salzler, M., MacKay, S.L., Moldawer, L.L., Lazarus, D.D. J. Immunol. (1997) [Pubmed]
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  16. Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Mirastschijski, U., Haaksma, C.J., Tomasek, J.J., Agren, M.S. Exp. Cell Res. (2004) [Pubmed]
  17. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Bendeck, M.P., Irvin, C., Reidy, M.A. Circ. Res. (1996) [Pubmed]
  18. The proprotein convertase PC5A and a metalloprotease are involved in the proteolytic processing of the neural adhesion molecule L1. Kalus, I., Schnegelsberg, B., Seidah, N.G., Kleene, R., Schachner, M. J. Biol. Chem. (2003) [Pubmed]
  19. Poly(ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death. Kauppinen, T.M., Swanson, R.A. J. Immunol. (2005) [Pubmed]
  20. Selective regulation of RNK-16 cell matrix metalloproteinases by the EP4 subtype of prostaglandin E2 receptor. Zeng, L., An, S., Goetzl, E.J. Biochemistry (1996) [Pubmed]
  21. Down-regulated expression of A disintegrin and metalloproteinase with thrombospondin-like repeats-1 by progesterone receptor antagonist is associated with impaired expansion of porcine cumulus-oocyte complexes. Shimada, M., Nishibori, M., Yamashita, Y., Ito, J., Mori, T., Richards, J.S. Endocrinology (2004) [Pubmed]
  22. Proteolytic cleavage of the neural cell adhesion molecule by ADAM17/TACE is involved in neurite outgrowth. Kalus, I., Bormann, U., Mzoughi, M., Schachner, M., Kleene, R. J. Neurochem. (2006) [Pubmed]
  23. In vitro evaluation of the angiostatic potential of drugs using an endothelialized tissue-engineered connective tissue. Tremblay, P.L., Berthod, F., Germain, L., Auger, F.A. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  24. EGF receptor transactivation mediates ANG II-stimulated mitogenesis in intestinal epithelial cells through the PI3-kinase/Akt/mTOR/p70S6K1 signaling pathway. Chiu, T., Santiskulvong, C., Rozengurt, E. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  25. Metalloproteinase shedding of Fas ligand regulates beta-amyloid neurotoxicity. Ethell, D.W., Kinloch, R., Green, D.R. Curr. Biol. (2002) [Pubmed]
  26. Autocrine EGF receptor activation mediates endothelial cell migration and vascular morphogenesis induced by VEGF under interstitial flow. Semino, C.E., Kamm, R.D., Lauffenburger, D.A. Exp. Cell Res. (2006) [Pubmed]
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  28. A matrix metalloproteinase inhibitor prevents processing of tumor necrosis factor alpha (TNF alpha) and abrogates endotoxin-induced lethality. Solorzano, C.C., Ksontini, R., Pruitt, J.H., Auffenberg, T., Tannahill, C., Galardy, R.E., Schultz, G.P., MacKay, S.L., Copeland, E.M., Moldawer, L.L. Shock (1997) [Pubmed]
  29. Prolonged antiscarring effects of ilomastat and MMC after experimental glaucoma filtration surgery. Wong, T.T., Mead, A.L., Khaw, P.T. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  30. Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle. Haas, T.L., Milkiewicz, M., Davis, S.J., Zhou, A.L., Egginton, S., Brown, M.D., Madri, J.A., Hudlicka, O. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
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