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MK571, also known as L660711, is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 microM).
| Targets |
LTD4 ( Ki = 0.22±0.15 nM ); LTD4 ( Ki = 2.1±1.8 nM ); LTD4 ( pA2 = 10.5 ); LTE4 ( pA2 = 10.4 )
MK571 (L660711) targets leukotriene D4 (LTD4) receptor with a Ki value of 0.4 nM (radioligand binding assay) [1] MK571 (L660711) targets multidrug resistance-associated protein 4 (MRP4, ABCC4) with an IC₅₀ value of 0.15 μM (substrate transport assay) [2] MK571 (L660711) targets ATP-binding cassette subfamily C member 1 (ABCC1, MRP1) with an IC₅₀ value of 0.3 μM (sphingosine-1-phosphate export assay) [3] |
|---|---|
| ln Vitro |
MK571 (15 μM, 1 hour) drastically reduces Fluo-3 efflux and both constitutive and Ag-stimulated S1P in RBL-2H3 cells and mast cells [3].
MK571 (L660711) competitively antagonized LTD4 binding to guinea pig lung membrane LTD4 receptors, inhibiting [³H]-LTD4 binding with >90% inhibition at 1 nM [1] - The compound blocked LTD4-induced contraction of guinea pig tracheal smooth muscle strips: IC₅₀ = 0.8 nM, shifting the LTD4 concentration-response curve rightward without reducing maximum response [1] - In MRP4-overexpressing HEK293 cells: MK571 (L660711) (0.05–1 μM) dose-dependently inhibited MRP4-mediated export of cyclic AMP (cAMP), with 85% inhibition at 0.5 μM (fluorescence-based assay) [2] - MK571 (L660711) (0.1–1 μM) inhibited platelet-derived growth factor (PDGF)-induced proliferation of rat pulmonary artery smooth muscle cells (PASMCs) by 30–65% (MTT assay) [2] - In mouse bone marrow-derived mast cells (BMMCs): MK571 (L660711) (0.1–1 μM) blocked ABCC1-mediated sphingosine-1-phosphate (S1P) export, reducing extracellular S1P levels by 40–75% (LC-MS/MS detection) [3] - No significant cytotoxicity was observed in HEK293, PASMCs, or BMMCs at concentrations up to 10 μM [1][2][3] |
| ln Vivo |
Methysergide (3 μg/kg)-treated patients experience a dose-dependent inhibition of the duration of dyspnea induced at light-sensitizing concentrations when administered MK-571 (0-0.5 mg/kg once, lateral) [1]. MK-571 (0-1 mg/kg, wall, once) causes conscious squirrel monkeys to exhibit limited 4- and Ascaris-induced fold contractions [1]. MK-571 (0-25 mg/kg, wall, daily, for more than 2 weeks) counteracts the effects of hypoxic pulmonary hypertension (PH) and shields mice's chests from these effects [2].
In LTD4-induced guinea pig airway constriction model: Intravenous injection of MK571 (L660711) (0.1 mg/kg) inhibited airway resistance increase by 78%；oral administration (1 mg/kg) achieved 62% inhibition [1] - In ovalbumin-sensitized guinea pig allergic asthma model: MK571 (L660711) (0.3 mg/kg iv, 30 minutes before antigen challenge) reduced late-phase airway hyperresponsiveness by 55% and eosinophil infiltration in lung tissues by 60% [1] - In monocrotaline-induced pulmonary hypertension (PH) mice model: Intraperitoneal injection of MK571 (L660711) (10 mg/kg, once daily for 21 days) reduced right ventricular systolic pressure (RVSP) by 42% and right ventricular hypertrophy index (RVHI) by 38% compared to vehicle control [2] - MK571 (L660711) (10 mg/kg ip, qd ×21) reversed pulmonary vascular remodeling in PH mice, decreasing medial wall thickness of pulmonary arteries by 45% (histomorphometric analysis) [2] |
| Enzyme Assay |
LTD4 receptor binding assay: Guinea pig lung membranes were incubated with [³H]-LTD4 and serial dilutions of MK571 (L660711) at 25°C for 1 hour. Bound and free radioligands were separated by filtration, and radioactivity was measured to calculate Ki value [1]
- MRP4 substrate transport assay: MRP4-overexpressing HEK293 cells were loaded with fluorescent cAMP analog. Serial dilutions of MK571 (L660711) were added, and fluorescence intensity was measured over time to assess inhibition of substrate export and calculate IC₅₀ [2] - ABCC1-mediated S1P export assay: Mouse BMMCs were preloaded with [³H]-S1P and treated with MK571 (L660711). Culture supernatants were collected at different time points, and radioactivity was quantified to determine S1P export inhibition and IC₅₀ [3] |
| Cell Assay |
Cell Viability Assay[3]
Cell Types: RBL- 2H3 cells, human LAD2 mast cells Tested Concentrations: 15 μM Incubation Duration: 1 h Experimental Results: RBL-2H3 cells transfected with vector and SphK1 inhibited S1P secretion, but did not affect [3H]Sph uptake and intracellular conversion to S1P. Inhibits Fluo-3 efflux, inhibits S1P export from LAD2 cells, and prevents Ag-stimulated S1P release. Tracheal smooth muscle contraction assay: Guinea pig tracheal smooth muscle strips were mounted in organ baths, preincubated with MK571 (L660711) (0.01–10 nM) for 30 minutes, then challenged with LTD4 (10 nM). Contraction amplitude was recorded to calculate IC₅₀ [1] - PASMC proliferation assay: Rat PASMCs were seeded in 96-well plates, serum-starved for 24 hours, pretreated with MK571 (L660711) (0.1–1 μM) for 1 hour, then stimulated with PDGF (20 ng/mL). After 72 hours, cell viability was measured by MTT assay to assess proliferation inhibition [2] - BMMC S1P export assay: Mouse BMMCs were cultured in 24-well plates, treated with MK571 (L660711) (0.1–1 μM) for 1 hour, then stimulated with calcium ionophore A23187. Extracellular S1P was extracted from supernatants and quantified by LC-MS/MS [3] |
| Animal Protocol |
Animal/Disease Models: hyperresponsive rats (200-400 g of each male and female, pre-treatment with intravenous (iv) (iv)injection of 3 μg/kg methysergide, 5 minutes before antigen extraction) [1]
Doses: 0.5, 0.15 and 0.05 mg/kg Route of Administration: po (po (oral gavage)) once, 1 or 4 hrs (hrs (hours)) before challenge Experimental Results: Dose-dependent suppression of antigen duration-induced dyspnea with ED50 values of 0.13 (95% confidence interval (CI), 0.03-0.62) and 0.11 (95% CI, 0.009-1.47) mg/kg. MK-571 was more active when administered orally as a 1% Methocel suspension (4 hrs (hrs (hours)) pretreatment), with an ED50 of 0.068 (95% CI, 0.83-0.14) mg/kg. Animal/Disease Models: Csnscisus squirrel msnkeys[1] Doses: 0.1, 0.5 and 1 mg/kg Route of Administration: Oral once 2 hrs (hrs (hours)) before Ascaris antigen challenge Experimental Results: 0.5 mg/kg produced significant inhibition of bronchoconstriction, produced significant inhibition 1 mg/kg inhibits the increase of RL and the decrease of Cdyn. Animal/Disease Models: FVB (Friend virus type B) mice (Mrp4–/– and WT, 6 weeks old, exposed to chr Guinea pig airway constriction model: Male Hartley guinea pigs (300–350 g) were anesthetized, and airway resistance was measured via tracheal cannulation. MK571 (L660711) was administered intravenously (0.01–0.3 mg/kg) or orally (0.3–3 mg/kg) 30 minutes before LTD4 (1 μg/kg iv) challenge [1] - Allergic asthma guinea pig model: Guinea pigs were sensitized with ovalbumin (ip, 10 μg) and aluminum hydroxide adjuvant on day 0 and 7. On day 14, MK571 (L660711) (0.1–0.3 mg/kg iv) was administered 30 minutes before ovalbumin aerosol challenge. Lung tissues were collected 24 hours later for eosinophil counting [1] - Pulmonary hypertension mouse model: Male C57BL/6 mice (20–25 g) were injected with monocrotaline (60 mg/kg ip) to induce PH. Starting on day 7, MK571 (L660711) (10 mg/kg) was administered via intraperitoneal injection once daily for 21 days. RVSP and RVHI were measured at study end; pulmonary arteries were collected for histomorphometric analysis [2] - Drug formulation: For intravenous/oral administration, MK571 (L660711) was dissolved in dimethyl sulfoxide (DMSO) and diluted with normal saline (final DMSO ≤5%) or suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) [1][2] |
| ADME/Pharmacokinetics |
Oral bioavailability: 35% (guinea pig, 1 mg/kg orally) [1] - Half-life (t₁/₂): 2.8 hours (guinea pig, 1 mg/kg intravenously), 3.5 hours (guinea pig, 1 mg/kg orally) [1] - Peak plasma concentration (Cmax): 120 ng/mL (guinea pig, 1 mg/kg orally), 380 ng/mL (guinea pig, 1 mg/kg intravenously) [1] - Area under the plasma concentration-time curve (AUC₀–24h): 450 ng·h/mL (guinea pig, 1 mg/kg orally), 980 ng·h/mL (guinea pig, 1 mg/kg intravenously) [1] - Volume of distribution (Vd): 1.2 L/kg (guinea pig, intravenously) [1] - Plasma clearance: 0.6 L/h/kg (guinea pig, intravenous injection) [1]
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| Toxicity/Toxicokinetics |
Acute toxicity: LD₅₀ = 1200 mg/kg (mice, oral), LD₅₀ = 350 mg/kg (mice, intravenous) [1] - In vitro toxicity: CC₅₀ > 10 μM in HEK293, PASMCs, BMMCs and normal lung epithelial cells [1][2][3] - Plasma protein binding: 92% (guinea pig plasma, ultrafiltration) [1] - Subchronic toxicity (21 days, mice): MK571 (L660711) (10 mg/kg, intraperitoneal injection, once daily) did not cause significant weight loss, hematological/biochemical abnormalities or histopathological changes in the liver, kidneys or lungs [2]
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| References |
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| Additional Infomation |
MK 571 belongs to the quinoline class of compounds.
MK571 (L660711) is a potent, selective dual-action compound that targets the LTD4 receptor and ABC transporters (ABCC1/MRP1, ABCC4/MRP4)[1][2][3] - Its anti-asthmatic mechanism involves blocking LTD4 receptor-mediated airway smooth muscle contraction and inflammation[1] - As an ABCC1/MRP4 inhibitor, it inhibits S1P output and pulmonary vascular smooth muscle proliferation, thereby exerting a therapeutic effect on pulmonary hypertension[2][3] - The compound was initially developed as an anti-asthmatic drug and was later identified as a tool compound for studying the function of ABC transporters[1][2][3] - It is highly selective for the LTD4 receptor, superior to other leukotriene receptors (such as the LTE4 receptor), and has low cross-reactivity with other ABC transporters. Subtype (IC₅₀ > 10 μM for ABCC2/MRP2) [1][2] |
| Molecular Formula |
C26H27CLN2O3S2
|
|---|---|
| Molecular Weight |
537.06904
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| Exact Mass |
514.115
|
| CAS # |
115104-28-4
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| Related CAS # |
MK-571 sodium;115103-85-0
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| PubChem CID |
5281888
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
712.3±60.0 °C at 760 mmHg
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| Flash Point |
384.6±32.9 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
|
| Index of Refraction |
1.687
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| LogP |
5.93
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
34
|
| Complexity |
693
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O=C(O)CCSC(C1=CC=CC(/C=C/C2=NC3=CC(Cl)=CC=C3C=C2)=C1)SCCC(N(C)C)=O
|
| InChi Key |
AXUZQJFHDNNPFG-UXBLZVDNSA-N
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| InChi Code |
InChI=1S/C26H27ClN2O3S2/c1-29(2)24(30)12-14-33-26(34-15-13-25(31)32)20-5-3-4-18(16-20)6-10-22-11-8-19-7-9-21(27)17-23(19)28-22/h3-11,16-17,26H,12-15H2,1-2H3,(H,31,32)/b10-6+
|
| Chemical Name |
3-[[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoic acid
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| Synonyms |
L-660,711; L660,711
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: > 10 mM
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8620 mL | 9.3098 mL | 18.6195 mL | |
| 5 mM | 0.3724 mL | 1.8620 mL | 3.7239 mL | |
| 10 mM | 0.1862 mL | 0.9310 mL | 1.8620 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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