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
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1798 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2540892 |
2.1 nM [Ki] | ||
Target ID: CHEMBL3004 |
2.8 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
PubMed
Title | Date | PubMed |
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Overexpression of the multidrug resistance-associated protein (MRP1) in human heavy metal-selected tumor cells. | 1999 Jan 29 |
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Characterization of the human cysteinyl leukotriene CysLT1 receptor. | 1999 Jun 24 |
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Differential sensitivities of MRP1-overexpressing lung tumor cells to cytotoxic metals. | 2000 Jan 3 |
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Molecular cloning and functional characterization of murine cysteinyl-leukotriene 1 (CysLT(1)) receptors. | 2001 Nov 1 |
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Carboxylesterase-mediated sensitization of human tumor cells to CPT-11 cannot override ABCG2-mediated drug resistance. | 2003 Aug |
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Functional expression of the multidrug resistance protein 1 in microglia. | 2003 Oct |
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Inverse agonist activity of selected ligands of the cysteinyl-leukotriene receptor 1. | 2004 Apr |
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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 |
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Modulation of MRP1 protein transport by plant, and synthetically modified flavonoids. | 2005 Aug 26 |
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MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice. | 2005 Feb 15 |
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Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). | 2005 Sep |
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Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation. | 2007 Oct 19 |
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Role of proline 1150 in functional interactions between the membrane spanning domains and nucleotide binding domains of the MRP1 (ABCC1) transporter. | 2008 Apr 15 |
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ABCC1, ABCC2 and ABCC3 are implicated in the transepithelial transport of the myco-estrogen zearalenone and its major metabolites. | 2009 Oct 28 |
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MRP transporters as membrane machinery in the bradykinin-inducible export of ATP. | 2010 Apr |
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Transcellular transport of aconitine across human intestinal Caco-2 cells. | 2013 Jul |
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Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells. | 2013 Jun |
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A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. | 2013 Nov |
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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 |
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Nrf2 Regulates the Sensitivity of Mouse Keratinocytes to Nitrogen Mustard via Multidrug Resistance-Associated Protein 1 (Mrp1). | 2016 Jan |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8389106
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
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/2540892
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 17:41:19 UTC 2023
by
admin
on
Fri Dec 15 17:41:19 UTC 2023
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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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C29712
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6509849
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CHEMBL280481
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C059141
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5Q9O54P0H7
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BB-80
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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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Related Record | Type | Details | ||
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SALT/SOLVATE -> PARENT | |||
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TARGET -> INHIBITOR |
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ACTIVE MOIETY |