MK-886
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MedKoo CAT#: 407217

CAS#: 118414-82-7 (free acid)

Description: MK-886, also known as L 663536, is a leukotriene antagonist. It may perform this by blocking the 5-lipoxygenase activating protein (FLAP), thus inhibiting 5-lipoxygenase (5-LOX), and may help in treating atherosclerosis. MK-886 inhibits cyclooxygenase-1 activity and suppresses platelet aggregation. MK-886 induces changes in cell cycle and increases apoptosis after photodynamic therapy with hypericin. MK-886 enhances tumour necrosis factor-alpha-induced differentiation and apoptosis.


Chemical Structure

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MK-886
CAS# 118414-82-7 (free acid)

Theoretical Analysis

MedKoo Cat#: 407217
Name: MK-886
CAS#: 118414-82-7 (free acid)
Chemical Formula: C27H34ClNO2S
Exact Mass: 471.20
Molecular Weight: 472.084
Elemental Analysis: C, 68.69; H, 7.26; Cl, 7.51; N, 2.97; O, 6.78; S, 6.79

Price and Availability

Size Price Availability Quantity
10mg USD 115 Same day
25mg USD 250 Same day
50mg USD 450 Same day
100mg USD 650 Same day
200mg USD 950 Same day
500mg USD 1650 Same day
1g USD 2750 Same day
2g USD 4650 Same day
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Related CAS #: 118414-82-7 (free acid)   118427-55-7 (sodium)   1049737-88-3 (sodium hydrate)    

Synonym: MK-886; MK886; MK 886; L-663,536; L663,536; L 663,536; L-663536; L663536; L 663536.

IUPAC/Chemical Name: 3-[3-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-propan-2-yl-indol-2-yl]-2,2 -dimethyl-propanoic acid

InChi Key: VFMGWQLOCZBFCK-UHFFFAOYSA-N

InChi Code: InChI=1S/C27H34ClNO2S/c1-6-7-14-32-25-22-15-20(18(2)3)10-13-23(22)29(17-19-8-11-21(28)12-9-19)24(25)16-27(4,5)26(30)31/h8-13,15,18H,6-7,14,16-17H2,1-5H3,(H,30,31)

SMILES Code: O=C(O)C(C)(C)CC(N1CC2=CC=C(Cl)C=C2)=C(SCCCC)C3=C1C=CC(C(C)C)=C3

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: MK-886 (L 663536) is a potent, cell-permeable and orally active FLAP (IC50 of 30 nM) and leukotriene biosynthesis (IC50s of 3 nM and 1.1 μM in intact leukocytes and human whole blood, respectively) inhibitor.
In vitro activity: The ability of MK886 to affect PPAR-α, -β and -γ activity was assessed using transient transfection reporter assays in CV-1 and keratinocyte 308 cell lines, and a stable transfection system in CV-1 cells. In all systems examined, 10 µM MK886 was able to inhibit Wy14,643 activation of PPARα by approx. 80% (Table 1). A dose–response study in keratinocyte 308 cells showed inhibition of 30³5, 65³7 and 70³8% at doses of 0.5, 1 and 5 µM MK886 respectively (n¯9). At doses between 10 and 20 µM, PPARα reporter assay activity levels were actually below the basal activity recorded in non-treated controls, suggesting inhibition of the endogenous PPARα. At doses over 20 µM, toxicity of MK886 precluded any useful measurements. MK886 also decreased PPARα activation by fatty acids in the stable transfection system (results not shown), indicating that its effect is not specific to activation by Wy14,643. Effects of MK886 on PPARβ activated with bezafibrate were substantial (48% inhibition) using the stable transfection assay in CV-1 cells, but were not evident using the transient transfection reporter assay in CV-1 cells or keratinocytes (Table 1), perhaps because of low reporter activity. Inhibition by MK886 of PPARγ activated with 15-deoxy-∆"#,"%-prostaglandin J# was also substantially lower than that seen with PPARα. The large standard error with PPARγ in the stable transfection system is a consequence of the very low activation achieved. The effect of MK886 on PPARα was also investigated in A549 human lung adenocarcinoma cells. There was no enhancement in reporter activity with activators of PPARβ and PPARγ using this cell line. As a result, it was not feasible to look at the effect of MK886 on PPARβ or PPARγ in this system. However, 20 µM MK886 did inhibit PPARα by 73% relative to levels seen following activation with 100 µM Wy14,643 (Table 2). Similar levels of inhibition were seen if activation was achieved with 50 µM Wy14,643 (results not shown). Reference: Biochem J. 2001 Jun 15;356(Pt 3):899-906. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/11389700/
In vivo activity: When administered in vivo MK-886 (L-663,536) was a potent inhibitor of antigen-induced dyspnea in inbred rats pretreated with methysergide (ED50, 0.036 mg/kg p.o.) and of Ascaris-induced bronchoconstriction in squirrel monkeys (1 mg/kg p.o.). The compound inhibited leukotriene biosynthesis in vivo in a rat pleurisy model (ED50, 0.2 mg/kg p.o.), an inflamed rat paw model (ED50, 0.8 mg/kg), a model of leukotriene excretion in rat bile following antigen provocation, and a model in the guinea-pig ear where leukotriene synthesis was induced by topical challenge with ionophore A23187 (ED50, 2.5 mg/kg p.o. and 0.6 micrograms topically). Reference: Can J Physiol Pharmacol. 1989 May;67(5):456-64. https://cdnsciencepub.com/doi/10.1139/y89-073?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 75.0 158.87

Preparing Stock Solutions

The following data is based on the product molecular weight 472.08 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol: 1. Kehrer JP, Biswal SS, La E, Thuillier P, Datta K, Fischer SM, Vanden Heuvel JP. Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886. Biochem J. 2001 Jun 15;356(Pt 3):899-906. doi: 10.1042/0264-6021:3560899. PMID: 11389700; PMCID: PMC1221919. 2. Gillard J, Ford-Hutchinson AW, Chan C, Charleson S, Denis D, Foster A, Fortin R, Leger S, McFarlane CS, Morton H, et al. L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2 - dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol. 1989 May;67(5):456-64. doi: 10.1139/y89-073. PMID: 2548691
In vivo protocol: 1. Gillard J, Ford-Hutchinson AW, Chan C, Charleson S, Denis D, Foster A, Fortin R, Leger S, McFarlane CS, Morton H, et al. L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2 - dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol. 1989 May;67(5):456-64. doi: 10.1139/y89-073. PMID: 2548691.

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1: Kuchárová B, Mikeš J, Jendželovský R, Vargová J, Mikešová L, Jendželovská Z, Kovaľ J, Fedoročko P. Potentiation of hypericin-mediated photodynamic therapy cytotoxicity by MK-886: Focus on ABC transporters, GDF-15 and redox status. Photodiagnosis Photodyn Ther. 2015 Sep;12(3):490-503. doi: 10.1016/j.pdpdt.2015.04.008. Epub 2015 May 21. PubMed PMID: 26003114.

2: Huang JK, Huang CC, Lu T, Chang HT, Lin KL, Tsai JY, Liao WC, Chien JM, Jan CR. Effect of MK-886 on Ca2+ level and viability in PC3 human prostate cancer cells. Basic Clin Pharmacol Toxicol. 2009 Jun;104(6):441-7. doi: 10.1111/j.1742-7843.2009.00413.x. Epub 2009 Apr 3. PubMed PMID: 19371256.

3: Koeberle A, Siemoneit U, Northoff H, Hofmann B, Schneider G, Werz O. MK-886, an inhibitor of the 5-lipoxygenase-activating protein, inhibits cyclooxygenase-1 activity and suppresses platelet aggregation. Eur J Pharmacol. 2009 Apr 17;608(1-3):84-90. doi: 10.1016/j.ejphar.2009.02.023. Epub 2009 Feb 23. PubMed PMID: 19239910.

4: Kleban J, Mikes J, Horváth V, Sacková V, Hofmanová J, Kozubík A, Fedorocko P. Mechanisms involved in the cell cycle and apoptosis of HT-29 cells pre-treated with MK-886 prior to photodynamic therapy with hypericin. J Photochem Photobiol B. 2008 Nov 13;93(2):108-18. doi: 10.1016/j.jphotobiol.2008.07.007. Epub 2008 Aug 6. PubMed PMID: 18771933.

5: Daglar G, Karaca T, Yuksek YN, Gozalan U, Akbiyik F, Sokmensuer C, Gurel B, Kama NA. Effect of montelukast and MK-886 on hepatic ischemia-reperfusion injury in rats. J Surg Res. 2009 May 1;153(1):31-8. doi: 10.1016/j.jss.2008.02.052. Epub 2008 Mar 26. PubMed PMID: 18656901.

6: Uz T, Dimitrijevic N, Imbesi M, Manev H, Manev R. Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice. Neurosci Lett. 2008 May 9;436(2):269-72. doi: 10.1016/j.neulet.2008.03.041. Epub 2008 Mar 21. PubMed PMID: 18403121; PubMed Central PMCID: PMC2423274.

7: Biserni A, Giannessi F, Sciarroni AF, Milazzo FM, Maggi A, Ciana P. In vivo imaging reveals selective peroxisome proliferator activated receptor modulator activity of the synthetic ligand 3-(1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886). Mol Pharmacol. 2008 May;73(5):1434-43. doi: 10.1124/mol.107.042689. Epub 2008 Feb 21. PubMed PMID: 18292206.

8: Imbesi M, Zavoreo I, Uz T, Sharma RP, Dimitrijevic N, Manev H, Manev R. 5-Lipoxygenase inhibitor MK-886 increases GluR1 phosphorylation in neuronal cultures in vitro and in the mouse cortex in vivo. Brain Res. 2007 May 25;1147:148-53. Epub 2007 Feb 14. PubMed PMID: 17349982.

9: Kleban J, Szilárdiová B, Mikes J, Horváth V, Sacková V, Brezáni P, Hofmanová J, Kozubík A, Fedorocko P. Pre-treatment of HT-29 cells with 5-LOX inhibitor (MK-886) induces changes in cell cycle and increases apoptosis after photodynamic therapy with hypericin. J Photochem Photobiol B. 2006 Aug 1;84(2):79-88. Epub 2006 Mar 20. PubMed PMID: 16545574.

10: Jawien J, Gajda M, Rudling M, Mateuszuk L, Olszanecki R, Guzik TJ, Cichocki T, Chlopicki S, Korbut R. Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice. Eur J Clin Invest. 2006 Mar;36(3):141-6. PubMed PMID: 16506957.

11: Stika J, Vondrácek J, Hofmanová J, Simek V, Kozubík A. MK-886 enhances tumour necrosis factor-alpha-induced differentiation and apoptosis. Cancer Lett. 2006 Jun 18;237(2):263-71. Epub 2005 Jul 21. PubMed PMID: 16039040.

12: Riendeau D, Aspiotis R, Ethier D, Gareau Y, Grimm EL, Guay J, Guiral S, Juteau H, Mancini JA, Méthot N, Rubin J, Friesen RW. Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886. Bioorg Med Chem Lett. 2005 Jul 15;15(14):3352-5. PubMed PMID: 15953724.

13: Anderson KM, Rubenstein M, Alrefai WA, Dudeja P, Tsui P, Guinan P, Harris JE. Reactive oxygen species and redox-induced programmed cell death due to MK 886: cells ("soil") "trump" agent ("seed"). In Vivo. 2005 Jan-Feb;19(1):109-18. PubMed PMID: 15796162.

14: Anderson KM, Rubenstein M, Tsui P, Harris JE. Disparate forms of MK 886-induced programmed death in BCL-2 (+) blood and BCL-2 (-) solid cancer cells and a putative "nuclear" Ca2+ channel: "soil" trumps "seed"? Med Hypotheses. 2005;64(2):307-11. PubMed PMID: 15607561.

15: Anderson KM, Rubenstein M, Alrefai WA, Dudeja P, Tsui P, Harris JE. Acute changes in U937 nuclear Ca2+ preceding type 1 "apoptotic" programmed cell death due to MK 886. Anticancer Res. 2004 Sep-Oct;24(5A):2601-15. PubMed PMID: 15517864.

16: Fan XM, Tu SP, Lam SK, Wang WP, Wu J, Wong WM, Yuen MF, Lin MC, Kung HF, Wong BC. Five-lipoxygenase-activating protein inhibitor MK-886 induces apoptosis in gastric cancer through upregulation of p27kip1 and bax. J Gastroenterol Hepatol. 2004 Jan;19(1):31-7. PubMed PMID: 14675240.

17: Anderson KM, Alrefai W, Bonomi P, Seed TM, Dudeja P, Hu Y, Harris JE. Caspase-dependent and -independent panc-1 cell death due to actinomycin D and MK 886 are additive but increase clonogenic survival. Exp Biol Med (Maywood). 2003 Sep;228(8):915-25. PubMed PMID: 12968063.

18: Stanke-Labesque F, Hardy G, Caron F, Cracowski JL, Bessard G. Inhibition of leukotriene synthesis with MK-886 prevents a rise in blood pressure and reduces noradrenaline-evoked contraction in L-NAME-treated rats. Br J Pharmacol. 2003 Sep;140(1):186-94. Epub 2003 Jul 29. PubMed PMID: 12967948; PubMed Central PMCID: PMC1574003.

19: Anderson KM, Alrefai W, Anderson C, Bonomi P, Harris J. MK 886 functions as a radiomimetic agent: genomic responses related to oxidative stress, the cell cycle, proliferation and programmed cell death in Panc-1 cells. Adv Exp Med Biol. 2002;507:451-6. PubMed PMID: 12664625.

20: Anderson KM, Alrefai WA, Dudeja PK, Jadko S, Bonomi P, Hu Y, Ou D, Harris JE. Increased cytosol Ca(2+) and type 1 programmed cell death in Bcl-2-positive U937 but not in Bcl-2-negative PC-3 and Panc-1 cells induced by the 5-lipoxygenase inhibitor MK 886. Prostaglandins Leukot Essent Fatty Acids. 2002 Apr;66(4):443-52. PubMed PMID: 12054916.