Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C26H26ClN2O3S2.Na |
| Molecular Weight | 537.069 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
[Na+].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=XNAYQOBPAXEYLI-LQKFMROPSA-M
InChI=1S/C26H27ClN2O3S2.Na/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);/q;+1/p-1/b10-6+;/t26-;/m1./s1
| Molecular Formula | Na |
| Molecular Weight | 22.9898 |
| Charge | 1 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
| Molecular Formula | C26H26ClN2O3S2 |
| Molecular Weight | 514.079 |
| Charge | -1 |
| 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
PubMed
| Title | Date | PubMed |
|---|---|---|
| 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 Feb 15 |
|
| Leukotriene D4-induced increases in cytosolic calcium in THP-1 cells: dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists. | 1994 Jun |
|
| Adenosine triphosphate-dependent transport of anionic conjugates by the rabbit multidrug resistance-associated protein Mrp2 expressed in insect cells. | 1998 Jun |
|
| Leukotrienes mediate murine bronchopulmonary hyperreactivity, inflammation, and part of mucosal metaplasia and tissue injury induced by recombinant murine interleukin-13. | 2003 Apr |
|
| Carboxylesterase-mediated sensitization of human tumor cells to CPT-11 cannot override ABCG2-mediated drug resistance. | 2003 Aug |
|
| Functional expression of the multidrug resistance protein 1 in microglia. | 2003 Oct |
|
| Leukotrienes mediate part of Ova-induced lung effects in mice via EGFR. | 2003 Oct |
|
| Inverse agonist activity of selected ligands of the cysteinyl-leukotriene receptor 1. | 2004 Apr |
|
| Structural requirements for the flavonoid-mediated modulation of glutathione S-transferase P1-1 and GS-X pump activity in MCF7 breast cancer cells. | 2004 Apr 15 |
|
| 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 Jun |
|
| Substrates and inhibitors of efflux proteins interfere with the MTT assay in cells and may lead to underestimation of drug toxicity. | 2004 Oct |
|
| The human multidrug-resistance-associated protein MRP1 mediates ATP-dependent transport of unconjugated bilirubin. | 2004 Oct 15 |
|
| 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 Sep 25 |
|
| Expression and activity of multidrug resistance protein 1 in a murine thymoma cell line. | 2005 Apr |
|
| Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes. | 2005 Aug 15 |
|
| Modulation of MRP1 protein transport by plant, and synthetically modified flavonoids. | 2005 Aug 26 |
|
| Inhibitory activity of a green tea extract and some of its constituents on multidrug resistance-associated protein 2 functionality. | 2005 Feb |
|
| MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice. | 2005 Feb 15 |
|
| Endogenous thiols and MRP transporters contribute to Hg2+ efflux in HgCl2-treated tubular MDCK cells. | 2005 Jan 5 |
|
| Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. | 2005 Jul |
|
| Combined effects of GSTP1 and MRP1 in melanoma drug resistance. | 2005 Jul 25 |
|
| Mrp2/Abcc2 transport activity is stimulated by protein kinase Calpha in a baculo virus co-expression system. | 2005 Jun 17 |
|
| Catfish egg lectin causes rapid activation of multidrug resistance 1 P-glycoprotein as a lipid translocase. | 2005 Mar |
|
| Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). | 2005 Sep |
|
| Inhibition of MRP1-mediated efflux in human erythrocytes by mono-anionic bile salts. | 2005 Sep-Oct |
|
| 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 Jan 1 |
|
| Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury. | 2006 Nov 21 |
|
| Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation. | 2007 Oct 19 |
|
| Role of proline 1150 in functional interactions between the membrane spanning domains and nucleotide binding domains of the MRP1 (ABCC1) transporter. | 2008 Apr 15 |
|
| Cysteinyl leukotrienes mediate the enhancing effects of indomethacin and aspirin on eosinophil production in murine bone marrow cultures. | 2008 Feb |
|
| A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. | 2008 Oct |
|
| Montelukast is a potent and durable inhibitor of multidrug resistance protein 2-mediated efflux of taxol and saquinavir. | 2009 Dec |
|
| CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides. | 2009 Feb 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 Jan |
|
| ABCC1, ABCC2 and ABCC3 are implicated in the transepithelial transport of the myco-estrogen zearalenone and its major metabolites. | 2009 Oct 28 |
|
| Culture period-dependent change of function and expression of ATP-binding cassette transporters in Caco-2 cells. | 2009 Sep |
|
| 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 |
|
| MRP transporters as membrane machinery in the bradykinin-inducible export of ATP. | 2010 Apr |
|
| Chrysin blocks topotecan-induced apoptosis in Caco-2 cells in spite of inhibition of ABC-transporters. | 2010 Aug 15 |
|
| Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. | 2010 Dec |
|
| Multidrug resistance proteins restrain the intestinal absorption of trans-resveratrol in rats. | 2010 Mar |
|
| Differential disposition of chenodeoxycholic acid versus taurocholic acid in response to acute troglitazone exposure in rat hepatocytes. | 2011 Apr |
|
| 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 Aug 15 |
|
| Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals. | 2011 May |
|
| Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). | 2013 Dec |
|
| 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 Feb 4 |
|
| Transcellular transport of aconitine across human intestinal Caco-2 cells. | 2013 Jul |
|
| Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells. | 2013 Jun |
|
| A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. | 2013 Nov |
|
| 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 Jun |
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
Fri Dec 15 15:55:21 GMT 2023
by
admin
on
Fri Dec 15 15:55:21 GMT 2023
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| Record UNII |
Q8W8588793
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| Record Status |
Validated (UNII)
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| Record Version |
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162377-77-7
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