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Chemical Compound Review

SureCN1807093     3-[3-butylsulfanyl-1-[(4...

Synonyms: AC1L2XXZ, LS-183392
 
 
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Disease relevance of MK-886

  • These studies indicate an important role of cysteinyl LTs in systemic anaphylaxis in vivo and demonstrate the blockade of anaphylactic LT generation by a novel inhibitor of LT biosynthesis (MK-886) but not by dexamethasone [1].
  • Finally, pertussis toxin and the 5-LO translocation inhibitor, MK-886, both blocked the IL-8-elicited 5-LO activation [2].
  • Intragastric administration of MK-886 prevented phorbol ester-induced ear edema, but not epidermal hyperproliferation and tumor promotion [3].
  • Suppression of intimal hyperplasia by a 5-lipoxygenase inhibitor, MK-886: studies with a photochemical model of endothelial injury [4].
  • 4. MK-886 did not inhibit the increased maximal RL produced by repeated antigen challenge, nor inhibit the airway eosinophilia induced by repeated antigen challenge [5].
 

High impact information on MK-886

  • Recently a compound, MK-886, has been described that blocks the synthesis of leukotrienes in intact activated leukocytes, but has little or no effect on enzymes involved in leukotriene synthesis, including 5-lipoxygenase, in cell-free systems [6].
  • A membrane protein with a high affinity for MK-886 and possibly representing the cellular target for MK-886 has been isolated from rat and human leukocytes [6].
  • A FLAP ligand, 3-[l-(4-chlorobenzyl)-3-t-butyl-thio-t-isopropylindol-2-yl]-2,2- dimethylpropanoic acid (MK-886), inhibited the acute angiotensin II and hypoxia-induced pulmonary vasoconstriction in vitro and the development of chronic hypoxic pulmonary hypertension in rats in vivo [7].
  • Although MK-886 inhibited LT synthesis in both cell types, it failed to prevent the translocation of 5-LO to the nuclear envelope [8].
  • Moreover, LTC4 synthase is inhibitable by a FLAP inhibitor, MK-886 [9].
 

Chemical compound and disease context of MK-886

 

Biological context of MK-886

 

Anatomical context of MK-886

  • When the assays were conducted in serum-free medium, both cell lines demonstrated increased DNA synthesis in response to NNK, an effect inhibited by the beta2-blocker, aspirin, or MK-886 [17].
  • This mast cell activity against the tachyzoites was inhibited by the 5-LO inhibitor A-63162 and the 5-LO-activating protein inhibitor MK-886 but not by the cyclooxygenase inhibitor indomethacin [18].
  • In cultured rat-derived smooth muscle cells, LTB4, an active metabolite of 5-lipoxygenase whose biosynthesis in air pouch exudate was suppressed by MK-886, stimulated cell migration [4].
  • NDGA is known to be a lipoxygenase inhibitor but other examples, like MK-886 and CDC, did not exert the same effects on differentiation of muscle cells, indicating that mechanisms of NDGA action are independent of its influence on lipoxygenase [19].
  • 6. At 100 nM compound MK-886 had no significant effects on calcium ion mobilization, superoxide anion production and actin polymerization in neutrophils [20].
 

Associations of MK-886 with other chemical compounds

  • LTB4 release in response to all stimuli tested was inhibited by MK-886, a drug that binds to 5-lipoxygenase-activating protein [21].
  • The stimulation of both 12(S)-HETE and 15(S)-HETE oxygenation by 5-LO is completely inhibitable by the FLAP inhibitor, MK-886 [22].
  • Because PGE synthase is a member of the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) family, of which leukotriene (LT) C(4) synthase and 5-lipoxygenase-activating protein are also members, we tested the effect of LTC(4) and the 5-lipoxygenase-activating protein inhibitor MK-886 on PGE synthase activity [23].
  • An indole class of leukotriene synthesis inhibitors, exemplified by MK-886, which does not directly inhibit 5-lipoxygenase, has been shown to bind to an 18-kDa leukocyte membrane protein and to inhibit 5-lipoxygenase membrane translocation [24].
  • Indomethacin abolished the incapacitation induced by CG in naive joints, but only the 5-lipoxygenase inhibitor MK-886 plus indomethacin blocked the response in primed joints [25].
 

Gene context of MK-886

  • No such redox-dependent effects were observed with the 5-LO inhibitor BWA4C, the 5-LO activating protein-inhibitor MK-886 or the pentacyclic triterpene acetyl-11-keto-beta-boswellic acid [26].
  • Treatment of PNG with the leukotriene-B4 inhibitor MK-886 prior to stimulation with M. tuberculosis or LAM partially blocked IL-8 and GRO-alpha induction, suggesting involvement of the 5-lipoxygenase pathway in the secretion of these chemokines [27].
  • However, MK-886 did inhibit IL-1beta-stimulated PGES activity in vitro by 86.8% [28].
  • In contrast, NS-398 did not inhibit VEGF production at 8 h, and only partially at 24 h, whereas MK-886 totally inhibited VEGF production at each time point [28].
  • We hypothesized that MK-886, an inhibitor of FLAP, could attenuate the development of atherosclerosis in the atherogenic apolipoprotein E/low density lipoprotein receptor (apoE/LDLR) double knockout (DKO) mouse model [29].
 

Analytical, diagnostic and therapeutic context of MK-886

  • Myeloperoxidase activity was measured and histological inflammation and damage were assessed at five days in control and infected animals and after treatment of infected animals with the LTB(4) synthesis inhibitor MK-886 [30].
  • Administration of A-79175 and MK-886 decreased the mean tumor volume by 64 and 44% respectively [15].
  • 3 Platelet deposition at the site of deep arterial wall injury averaged 56.4+/-11.0x10(6) platelets cm(-2) in the control group, and was significantly reduced to 18.2+/-3.8x10(6) platelets cm(-2) (P<0.005) by treatment with MK-886 [31].
  • Therefore, we investigated the effects of the selective leukotriene biosynthesis inhibitor 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid (MK-886) on the acute thrombotic and vasomotor responses after arterial injury by angioplasty [31].
  • 2 Carotid arterial injury was produced by balloon dilatation in control (molecusol vehicle; n=10) and treated (MK-886, 10 mg kg(-1), i.v.; n=9) pigs [31].

References

  1. Prevention of endogenous leukotriene production during anaphylaxis in the guinea pig by an inhibitor of leukotriene biosynthesis (MK-886) but not by dexamethasone. Guhlmann, A., Keppler, A., Kästner, S., Krieter, H., Brückner, U.B., Messmer, K., Keppler, D. J. Exp. Med. (1989) [Pubmed]
  2. Induction by chemokines of lipid mediator synthesis in granulocyte-macrophage colony-stimulating factor-treated human neutrophils. McDonald, P.P., Pouliot, M., Borgeat, P., McColl, S.R. J. Immunol. (1993) [Pubmed]
  3. Phorbol ester-induced leukotriene biosynthesis and tumor promotion in mouse epidermis. Fürstenberger, G., Csuk-Glänzer, B.I., Marks, F., Keppler, D. Carcinogenesis (1994) [Pubmed]
  4. Suppression of intimal hyperplasia by a 5-lipoxygenase inhibitor, MK-886: studies with a photochemical model of endothelial injury. Kondo, K., Umemura, K., Ohmura, T., Hashimoto, H., Nakashima, M. Thromb. Haemost. (1998) [Pubmed]
  5. Role of leukotrienes in airway hyperresponsiveness in guinea-pigs. Ishida, K., Thomson, R.J., Schellenberg, R.R. Br. J. Pharmacol. (1993) [Pubmed]
  6. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Dixon, R.A., Diehl, R.E., Opas, E., Rands, E., Vickers, P.J., Evans, J.F., Gillard, J.W., Miller, D.K. Nature (1990) [Pubmed]
  7. Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats. Voelkel, N.F., Tuder, R.M., Wade, K., Höper, M., Lepley, R.A., Goulet, J.L., Koller, B.H., Fitzpatrick, F. J. Clin. Invest. (1996) [Pubmed]
  8. 5-Lipoxygenase is located in the euchromatin of the nucleus in resting human alveolar macrophages and translocates to the nuclear envelope upon cell activation. Woods, J.W., Coffey, M.J., Brock, T.G., Singer, I.I., Peters-Golden, M. J. Clin. Invest. (1995) [Pubmed]
  9. Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Lam, B.K., Penrose, J.F., Freeman, G.J., Austen, K.F. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  10. Activation of the human neutrophil 5-lipoxygenase by leukotriene B4. McDonald, P.P., McColl, S.R., Naccache, P.H., Borgeat, P. Br. J. Pharmacol. (1992) [Pubmed]
  11. Chronic leukotriene inhibition in the rat fails to modify the toxicological effects of a cyclooxygenase inhibitor. Ford-Hutchinson, A.W., Tagari, P., Ching, S.V., Anderson, C.A., Coleman, J.B., Peter, C.P. Can. J. Physiol. Pharmacol. (1993) [Pubmed]
  12. Opposing and hierarchical roles of leukotrienes in local innate immune versus vascular responses in a model of sepsis. Benjamim, C.F., Canetti, C., Cunha, F.Q., Kunkel, S.L., Peters-Golden, M. J. Immunol. (2005) [Pubmed]
  13. In vitro airway and tissue response to antigen in sensitized rats. Role of serotonin and leukotriene D4. Nagase, T., Fukuchi, Y., Dallaire, M.J., Martin, J.G., Ludwig, M.S. Am. J. Respir. Crit. Care Med. (1995) [Pubmed]
  14. Biochemical activity, pharmacokinetics, and tolerability of MK-886, a leukotriene biosynthesis inhibitor, in humans. Depre, M., Friedman, B., Tanaka, W., Van Hecken, A., Buntinx, A., DeSchepper, P.J. Clin. Pharmacol. Ther. (1993) [Pubmed]
  15. Inhibitors of lipoxygenase: a new class of cancer chemopreventive agents. Rioux, N., Castonguay, A. Carcinogenesis (1998) [Pubmed]
  16. 5-Lipoxygenase reaction products modulate alveolar macrophage phagocytosis of Klebsiella pneumoniae. Mancuso, P., Standiford, T.J., Marshall, T., Peters-Golden, M. Infect. Immun. (1998) [Pubmed]
  17. Beta-adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas. Weddle, D.L., Tithoff, P., Williams, M., Schuller, H.M. Carcinogenesis (2001) [Pubmed]
  18. The importance of leukotrienes in mast cell-mediated Toxoplasma gondii cytotoxicity. Henderson, W.R., Chi, E.Y. J. Infect. Dis. (1998) [Pubmed]
  19. Nordihydroguaiaretic acid (NDGA) blocks the differentiation of C2C12 myoblast cells. Ito, H., Ueda, H., Iwamoto, I., Inaguma, Y., Takizawa, T., Asano, T., Kato, K. J. Cell. Physiol. (2005) [Pubmed]
  20. Inhibitory effects of MK-886 on arachidonic acid metabolism in human phagocytes. Ménard, L., Pilote, S., Naccache, P.H., Laviolette, M., Borgeat, P. Br. J. Pharmacol. (1990) [Pubmed]
  21. Calcium-dependent eicosanoid metabolism by concanavalin A-stimulated human monocytes in vitro. Synergism with phorbol ester indicates separate regulation of leukotriene B4 synthesis and release. Hoffman, T., Brando, C., Lizzio, E.F., Lee, Y.L., Hansen, M., Tripathi, A.K., Taplits, M., Puri, J., Bonvini, E., Abrahamsen, T.G. J. Immunol. (1991) [Pubmed]
  22. Cellular oxygenation of 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid by 5-lipoxygenase is stimulated by 5-lipoxygenase-activating protein. Mancini, J.A., Waterman, H., Riendeau, D. J. Biol. Chem. (1998) [Pubmed]
  23. Cloning, expression, and up-regulation of inducible rat prostaglandin e synthase during lipopolysaccharide-induced pyresis and adjuvant-induced arthritis. Mancini, J.A., Blood, K., Guay, J., Gordon, R., Claveau, D., Chan, C.C., Riendeau, D. J. Biol. Chem. (2001) [Pubmed]
  24. 5-Lipoxygenase-activating protein is the target of a quinoline class of leukotriene synthesis inhibitors. Evans, J.F., Lévillé, C., Mancini, J.A., Prasit, P., Thérien, M., Zamboni, R., Gauthier, J.Y., Fortin, R., Charleson, P., MacIntyre, D.E. Mol. Pharmacol. (1991) [Pubmed]
  25. Tumour necrosis factor-alpha mediates carrageenin-induced knee-joint incapacitation and also triggers overt nociception in previously inflamed rat knee-joints. Tonussi, C.R., Ferreira, S.H. Pain (1999) [Pubmed]
  26. Nonredox 5-lipoxygenase inhibitors require glutathione peroxidase for efficient inhibition of 5-lipoxygenase activity. Werz, O., Szellas, D., Henseler, M., Steinhilber, D. Mol. Pharmacol. (1998) [Pubmed]
  27. Chemokine secretion by human polymorphonuclear granulocytes after stimulation with Mycobacterium tuberculosis and lipoarabinomannan. Riedel, D.D., Kaufmann, S.H. Infect. Immun. (1997) [Pubmed]
  28. Induced microsomal PGE synthase-1 is involved in cyclooxygenase-2-dependent PGE2 production in gastric fibroblasts. Shinji, Y., Tsukui, T., Tatsuguchi, A., Shinoki, K., Kusunoki, M., Suzuki, K., Hiratsuka, T., Wada, K., Futagami, S., Miyake, K., Gudis, K., Sakamoto, C. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  29. Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice. Jawien, J., Gajda, M., Rudling, M., Mateuszuk, L., Olszanecki, R., Guzik, T.J., Cichocki, T., Chlopicki, S., Korbut, R. Eur. J. Clin. Invest. (2006) [Pubmed]
  30. Do eicosanoids cause colonic dysfunction in experimental E coli O157:H7 (EHEC) infection? Bell, C.J., Elliott, E.J., Wallace, J.L., Redmond, D.M., Payne, J., Li, Z., O'Loughlin, E.V. Gut (2000) [Pubmed]
  31. Platelets, neutrophils, and vasoconstriction after arterial injury by angioplasty in pigs: effects of MK-886, a leukotriene biosynthesis inhibitor. Provost, P., Borgeat, P., Merhi, Y. Br. J. Pharmacol. (1998) [Pubmed]
 
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