Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C26H27ClN2O3S2 |
| Molecular Weight | 515.087 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CN(C)C(=O)CCS[C@H](SCCC(O)=O)C1=CC(\C=C\C2=NC3=CC(Cl)=CC=C3C=C2)=CC=C1
InChI
InChIKey=AXUZQJFHDNNPFG-LHAVAQOQSA-N
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+/t26-/m1/s1
| Molecular Formula | C26H27ClN2O3S2 |
| Molecular Weight | 515.087 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 1 |
| Optical Activity | UNSPECIFIED |
A potent, selective and orally active receptor antagonist of leukotriene D4, verlukast (MK-571), was discovered and developed from a styrylquinoline lead structure based on a hypothetical model of the leukotriene D4 receptor. MK-571 blocks the action of LTD4 in animals and man, and is effective in a number of animal models of antigen-induced bronchoconstriction at plasma concentration at or below 2 ug/mL. MK-571 also blocks antigen-induced asthmatic responses in man. MK-571 is a potent and selective leukotriene D4 (LTD4) antagonist and ABCC multidrug resistance protein 1(MRP1) inhibitor. The cysteinyl leukotrienes (CysLTs), LTC4, LTD4, and LTE4, mediate their actions through two distinct G-protein coupled receptors. LTD4 is the preferred ligand for the CysLT1 receptor, whereas LTC4 and LTD4 bind with approximately equal affinity to the CysLT2 receptor. MK-571 is a selective, orally active CysLT1 receptor antagonist. It blocks the binding of LTD4, but not LTC4, to human and guinea pig lung membranes with Ki values of 0.22 nM and 2.1 nM, respectively. MK-571 effectively blocks LTD4 activation of recombinant human and mouse CysLT1 receptors but is ineffective at blocking LTC4 or LTD4 activation of the recombinant human or murine CysLT2 receptors.
Originator
Sources: http://adisinsight.springer.com/drugs/800001553 | https://www.ncbi.nlm.nih.gov/pubmed/1793062
Curator's Comment: # Merck & Co
Approval Year
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
6.7 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12959296/ |
75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered: |
VERLUKAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
41.3 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12959296/ |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
VERLUKAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
32.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12959296/ |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
VERLUKAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
19.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12959296/ |
75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered: |
VERLUKAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
159.4 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12959296/ |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
VERLUKAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
138.8 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12959296/ |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
VERLUKAST plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
Doses
| Dose | Population | Adverse events |
|---|---|---|
1500 mg single, intravenous Highest studied dose Dose: 1500 mg Route: intravenous Route: single Dose: 1500 mg Sources: |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: |
Other AEs: Loose stool... |
600 mg 3 times / day multiple, oral Highest studied dose Dose: 600 mg, 3 times / day Route: oral Route: multiple Dose: 600 mg, 3 times / day Sources: |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: |
Other AEs: Loose stools, Diarrhoea... Other AEs: Loose stools (grade 1-2) Sources: Diarrhoea (grade 1-2) Cramps (grade 1-2) |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Loose stool | 8.3% | 1500 mg single, intravenous Highest studied dose Dose: 1500 mg Route: intravenous Route: single Dose: 1500 mg Sources: |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: |
| Cramps | grade 1-2 | 600 mg 3 times / day multiple, oral Highest studied dose Dose: 600 mg, 3 times / day Route: oral Route: multiple Dose: 600 mg, 3 times / day Sources: |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: |
| Diarrhoea | grade 1-2 | 600 mg 3 times / day multiple, oral Highest studied dose Dose: 600 mg, 3 times / day Route: oral Route: multiple Dose: 600 mg, 3 times / day Sources: |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: |
| Loose stools | grade 1-2 | 600 mg 3 times / day multiple, oral Highest studied dose Dose: 600 mg, 3 times / day Route: oral Route: multiple Dose: 600 mg, 3 times / day Sources: |
healthy, ADULT Health Status: healthy Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| yes [IC50 2.8 uM] | ||||
| yes [Inhibition 10 uM] | ||||
| yes |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| yes | ||||
| yes |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Nrf2 Regulates the Sensitivity of Mouse Keratinocytes to Nitrogen Mustard via Multidrug Resistance-Associated Protein 1 (Mrp1). | 2016-01 |
|
| Utilization of human nuclear receptors as an early counter screen for off-target activity: a case study with a compendium of 615 known drugs. | 2015-06 |
|
| Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). | 2013-12 |
|
| A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. | 2013-11 |
|
| Transcellular transport of aconitine across human intestinal Caco-2 cells. | 2013-07 |
|
| Arsenate accumulation and arsenate-induced glutathione export in astrocyte-rich primary cultures. | 2013-06 |
|
| Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells. | 2013-06 |
|
| The role of efflux transporters on the transport of highly toxic aconitine, mesaconitine, hypaconitine, and their hydrolysates, as determined in cultured Caco-2 and transfected MDCKII cells. | 2013-02-04 |
|
| Multidrug resistance-associated protein 1 mediates 15-deoxy-Δ(12,14)-prostaglandin J2-induced expression of glutamate cysteine ligase expression via Nrf2 signaling in human breast cancer cells. | 2011-08-15 |
|
| Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals. | 2011-05 |
|
| Differential disposition of chenodeoxycholic acid versus taurocholic acid in response to acute troglitazone exposure in rat hepatocytes. | 2011-04 |
|
| Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. | 2010-12 |
|
| Chrysin blocks topotecan-induced apoptosis in Caco-2 cells in spite of inhibition of ABC-transporters. | 2010-08-15 |
|
| MRP transporters as membrane machinery in the bradykinin-inducible export of ATP. | 2010-04 |
|
| Multidrug resistance proteins restrain the intestinal absorption of trans-resveratrol in rats. | 2010-03 |
|
| Multidrug resistance protein transporter and Ins(1,4,5)P₃-sensitive Ca²+-signaling involved in adenosine triphosphate export via Gq protein-coupled NK₂-receptor stimulation with neurokinin A. | 2010 |
|
| Montelukast is a potent and durable inhibitor of multidrug resistance protein 2-mediated efflux of taxol and saquinavir. | 2009-12 |
|
| ABCC1, ABCC2 and ABCC3 are implicated in the transepithelial transport of the myco-estrogen zearalenone and its major metabolites. | 2009-10-28 |
|
| Culture period-dependent change of function and expression of ATP-binding cassette transporters in Caco-2 cells. | 2009-09 |
|
| CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides. | 2009-02-10 |
|
| Cross-functioning between the extraneuronal monoamine transporter and multidrug resistance protein 1 in the uptake of adrenaline and export of 5-(glutathion-S-yl)adrenaline in rat cardiomyocytes. | 2009-01 |
|
| A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. | 2008-10 |
|
| Role of proline 1150 in functional interactions between the membrane spanning domains and nucleotide binding domains of the MRP1 (ABCC1) transporter. | 2008-04-15 |
|
| Cysteinyl leukotrienes mediate the enhancing effects of indomethacin and aspirin on eosinophil production in murine bone marrow cultures. | 2008-02 |
|
| Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation. | 2007-10-19 |
|
| Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury. | 2006-11-21 |
|
| Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells. | 2006-01-01 |
|
| Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). | 2005-09 |
|
| Modulation of MRP1 protein transport by plant, and synthetically modified flavonoids. | 2005-08-26 |
|
| Inhibition of MRP1-mediated efflux in human erythrocytes by mono-anionic bile salts. | 2005-08-17 |
|
| Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes. | 2005-08-15 |
|
| Combined effects of GSTP1 and MRP1 in melanoma drug resistance. | 2005-07-25 |
|
| Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. | 2005-07 |
|
| Mrp2/Abcc2 transport activity is stimulated by protein kinase Calpha in a baculo virus co-expression system. | 2005-06-17 |
|
| Expression and activity of multidrug resistance protein 1 in a murine thymoma cell line. | 2005-04 |
|
| Catfish egg lectin causes rapid activation of multidrug resistance 1 P-glycoprotein as a lipid translocase. | 2005-03 |
|
| MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice. | 2005-02-15 |
|
| Inhibitory activity of a green tea extract and some of its constituents on multidrug resistance-associated protein 2 functionality. | 2005-02 |
|
| Endogenous thiols and MRP transporters contribute to Hg2+ efflux in HgCl2-treated tubular MDCK cells. | 2005-01-05 |
|
| The human multidrug-resistance-associated protein MRP1 mediates ATP-dependent transport of unconjugated bilirubin. | 2004-10-15 |
|
| Substrates and inhibitors of efflux proteins interfere with the MTT assay in cells and may lead to underestimation of drug toxicity. | 2004-10 |
|
| Determination of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid and its acyl glucuronide in Caco-2 monolayers by liquid chromatography with fluorescence detection: application to transport studies. | 2004-09-25 |
|
| Identification of multidrug resistance-associated protein 1 and glutathione as multidrug resistance mechanisms in human prostate cancer cells: chemosensitization with leukotriene D4 antagonists and buthionine sulfoximine. | 2004-06 |
|
| Structural requirements for the flavonoid-mediated modulation of glutathione S-transferase P1-1 and GS-X pump activity in MCF7 breast cancer cells. | 2004-04-15 |
|
| Inverse agonist activity of selected ligands of the cysteinyl-leukotriene receptor 1. | 2004-04 |
|
| Functional expression of the multidrug resistance protein 1 in microglia. | 2003-10 |
|
| Adenosine triphosphate-dependent transport of anionic conjugates by the rabbit multidrug resistance-associated protein Mrp2 expressed in insect cells. | 1998-06 |
|
| Leukotriene D4-induced increases in cytosolic calcium in THP-1 cells: dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists. | 1994-06 |
|
| Effect of the leukotriene receptor antagonist MK-0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects. | 1993-12 |
|
| Characterization of the leukotriene D4 receptor in dimethylsulphoxide-differentiated U937 cells: comparison with the leukotriene D4 receptor in human lung and guinea-pig lung. | 1993-02-15 |
Sample Use Guides
In a three-period, randomized, double-blind, crossover study, single doses of verlukast, 125 and 500 mg, and placebo were given intravenously by bolus infusion to nine patients with moderate, stable asthma (FEV1 40 to 80% predicted) on individual study days separated by a week.
Route of Administration:
Intravenous
Verlukast (5.8 x 10(-8)M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio less than 2). L-660,711 (1.9 x 10(-5)M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2 alpha, U-44069, or PGD2.
| Substance Class |
Chemical
Created
by
admin
on
Edited
Mon Mar 31 18:50:26 GMT 2025
by
admin
on
Mon Mar 31 18:50:26 GMT 2025
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| Record UNII |
5Q9O54P0H7
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| Record Status |
Validated (UNII)
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| Record Version |
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NCI_THESAURUS |
C29712
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6509849
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CHEMBL280481
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C059141
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120443-16-5
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C96714
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100000079081
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SUB00041MIG
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6776
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SALT/SOLVATE -> PARENT | |||
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ACTIVE MOIETY |
