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MK886 (also known as L663536) is a novel and potent 5-lipoxygenase-activating protein inhibitor and a leukotriene biosynthesis inhibitor (IC50=2.5 nM). MK-886 acts 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.
Physicochemical Properties
| Molecular Formula | C27H34CLNO2S |
| Molecular Weight | 472.0824 |
| Exact Mass | 471.20 |
| Elemental Analysis | C, 68.69; H, 7.26; Cl, 7.51; N, 2.97; O, 6.78; S, 6.79 |
| CAS # | 118414-82-7 |
| Related CAS # | MK-886 sodium salt;118427-55-7; 118414-82-7 (free acid); 1049737-88-3 (sodium hydrate) |
| PubChem CID | 3651377 |
| Appearance | Typically exists as White to off-white solids at room temperature |
| Density | 1.14g/cm3 |
| Boiling Point | 623.4ºC at 760mmHg |
| Melting Point | 295-297ºC |
| Flash Point | 330.8ºC |
| Vapour Pressure | 2.11E-16mmHg at 25°C |
| Index of Refraction | 1.58 |
| LogP | 6.675 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 32 |
| Complexity | 638 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | ClC1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])N1C2C([H])=C([H])C(C([H])(C([H])([H])[H])C([H])([H])[H])=C([H])C=2C(=C1C([H])([H])C(C(=O)O[H])(C([H])([H])[H])C([H])([H])[H])SC(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] |
| 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) |
| Chemical Name | 3-[3-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-propan-2-yl-indol-2-yl]-2,2 -dimethyl-propanoic acid |
| Synonyms | L-663,536; MK 886; L663,536; MK886; L-663536; L 663,536; MK-886; L663536; MK-886; MK 886; 3-(3-(tert-butylthio)-1-(4-chlorobenzyl)-5-isopropyl-1H-indol-2-yl)-2,2-dimethylpropanoic acid; MK886; 3-[3-tert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-propan-2-ylindol-2-yl]-2,2-dimethylpropanoic acid; L-663,536; 3-[3-(tert-butylsulfanyl)-1-[(4-chlorophenyl)methyl]-5-(propan-2-yl)-1H-indol-2-yl]-2,2-dimethylpropanoic acid; L 663536. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | FLAP (IC50 = 30 nM); PPARα |
| ln Vitro | In primary mouse keratinocyte cultures, MK-886 (0.5-2 μM; 15 hours; primary keratinocytes) treatment decreases keratin-1 expression [1]. 10 μM MK-886 was found to be able to suppress the activation of PPARα by Wy-14643 by around 80% in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells, and human lung adenocarcinoma A549 cells using a transient transfection technique. In stable transfection systems, MK-886 can also lessen the activation of PPARα by fatty acids [1]. MK-886-induced apoptosis cannot be stopped by PPARα and PPARγ agonists, despite the fact that Jurkat cells express all PPAR isoforms [1]. |
| ln Vivo | Methysergide-pretreated inbred rats' antigen-induced dyspnea is successfully inhibited by MK-886 (L 663536; 5 mg/kg; oral; male Sprague-Dawley rats) treatment [2]. ?In rat pleurisy (ED50, 0.2 mg/kg po), inflammatory paw (ED50, 0.8 mg/kg), and rat biliary leukotriene excretion models, MK-886 (L 663536) reduces leukotriene excretion in vivo. Triene biosynthesis elicitation of antigen [2]. |
| Enzyme Assay | PPAR ligand binding assay: Binding of MK886 to PPARs was determined using the coactivator-dependent receptor ligand assay (CARLA). A construct containing the PPARα ligand binding domain cloned in frame with glutathione S-transferase (GST) was procured from Walter Wahli. The GST–PPAR ligand binding domain fusion protein was expressed in Escherichia coli BL2 DE3 (pLysS). Bacterial pellets containing the fusion protein were resuspended in 10 ml of lysis buffer [PBS containing 1% (v}v) Triton X-100 and 0.5 mM PMSF] and lysed by repeated freeze–thawing. DNA and insoluble matter were removed by centrifugation at 4500 g. The fusion protein was purified using GSH–Sepharose beads at 4 °C, washed three times in lysis buffer, and equilibrated in 20 mM Tris}HCl (pH 8.0), 100 mM NaCl, 1 mM EDTA, 0.5% Nonidet P-40 and 1 mM dithiothreitol (DTT) supplemented with 1% (w}v) dry milk. The amount of protein used per reaction was 1–3 µg. The beads were incubated with different concentrations of MK886 and $&S-radiolabelled steroid receptor coactivator-1 (SRC-1) prepared with a pSG5 plasmid construct that can express SRC-1 (procured from Walter Wahli) in itro using a coupled transcription}translation rabbit reticulocyte lysate system. Labelling was achieved by incubating for 1 h in the presence of [$&S]methionine, and the beads were recovered by centrifugation. The beads were then washed and analysed for interaction with SRC-1 using SDS}PAGE. Coomassie Brilliant Blue staining of GST–ligand binding domain fusions allowed standardization between different reactions. The SRC-1 protein complex was visualized by autoradiography. Relative band densities were determined using a scanned image and UN-SCAN-IT software[1]. |
| Cell Assay |
Western Blot Analysis[1] Cell Types: Primary Keratinocytes Tested Concentrations: 0.5 µM, 1 µM or 2 µM Incubation Duration: 15 hrs (hours) Experimental Results: diminished keratin-1 expression. |
| Animal Protocol |
Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (300-400 g), antigen-induced dyspnea [1] Doses: 5 mg/kg Route of Administration: Oral Experimental Results:Inhibition of antigen-induced dyspnea. |
| References |
[1]. Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886. Biochem J. 2001 Jun 15;356(Pt 3):899-906. [2]. 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. [3]. Mancini JA, et al. 5-Lipoxygenase-activating protein is the target of a novel hybrid of two classes of leukotriene biosynthesis inhibitors. Mol Pharmacol. 1992 Feb;41(2):267-72. |
| Additional Infomation |
3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-(propan-2-yl)-1H-indol-2-yl]-2,2-dimethylpropanoic acid is a member of the class of indoles that is 1H-indole substituted by a isopropyl group at position 5, a tert-butylsulfanediyl group at position 3, a 4-chlorobenzyl group at position 1 and a 2-carboxy-2-methylpropyl group at position 2. It acts as an inhibitor of arachidonate 5-lipoxygenase. It has a role as an EC 1.13.11.34 (arachidonate 5-lipoxygenase) inhibitor, an antineoplastic agent and a leukotriene antagonist. It is an aryl sulfide, a member of indoles, a monocarboxylic acid and a member of monochlorobenzenes. MK-886 is an experimental inhibitor of leukotriene synthesis. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~75 mg/mL (~158.87 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.30 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (4.41 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10 mg/mL (21.18 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1183 mL | 10.5914 mL | 21.1829 mL | |
| 5 mM | 0.4237 mL | 2.1183 mL | 4.2366 mL | |
| 10 mM | 0.2118 mL | 1.0591 mL | 2.1183 mL |