Identification
NameElacridar
Accession NumberDB04881
TypeSmall Molecule
GroupsInvestigational
Description

Elacridar (GW120918) is an oral bioenhancer that targets multiple drug resistance in tumors. In many cases, the appearance of multidrug resistance in cancer is due to a change in expression of protein inhibitors. As of August 2007 elacridar was not listed on GSK's product pipeline. Development is assumed to have been discontinued.

Structure
Thumb
SynonymsNot Available
External IDs LY-335979 / LY335979
Product Ingredients
IngredientUNIICASInChI KeyDetails
Elacridar hydrochlorideNX2BHH1A5B 143851-98-3IQOJZZHRYSSFJM-UHFFFAOYSA-NDetails
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNIIN488540F94
CAS number143664-11-3
WeightAverage: 563.6429
Monoisotopic: 563.242021181
Chemical FormulaC34H33N3O5
InChI KeyOSFCMRGOZNQUSW-UHFFFAOYSA-N
InChI
InChI=1S/C34H33N3O5/c1-40-28-9-5-7-26-32(28)36-31-25(33(26)38)6-4-8-27(31)34(39)35-24-12-10-21(11-13-24)14-16-37-17-15-22-18-29(41-2)30(42-3)19-23(22)20-37/h4-13,18-19H,14-17,20H2,1-3H3,(H,35,39)(H,36,38)
IUPAC Name
N-{4-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]phenyl}-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamide
SMILES
COC1=CC=CC2=C1NC1=C(C=CC=C1C(=O)NC1=CC=C(CCN3CCC4=CC(OC)=C(OC)C=C4C3)C=C1)C2=O
Pharmacology
Indication

For the treatment of solid tumors.

Structured Indications Not Available
Pharmacodynamics

Elacridar is an oral bioenhancer that targets multiple drug resistance in tumors. In many cases, the appearance of multidrug resistance in cancer is due to a change in expression of protein inhibitors.

Mechanism of action

P-glycoprotein is a well characterized human ABC-transporter of the MDR/TAP subfamily. It is an ATP-dependent efflux pump with broad substrate specificity. It likely evolved as a defence mechanism against harmful substances. Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Thus, there is a reduced bioavailability, therapeutic plasma concentrations are not attained. Elacridar functions by inhibiting P-glycoprotein, resulting in an increased bioavailability of coadminstered drugs.

TargetKindPharmacological actionActionsOrganismUniProt ID
Multidrug resistance protein 1ProteinunknownNot AvailableHumanP08183 details
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Elacridar.Approved
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Elacridar.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Hubensack M, Muller C, Hocherl P, Fellner S, Spruss T, Bernhardt G, Buschauer A: Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. J Cancer Res Clin Oncol. 2008 May;134(5):597-607. Epub 2007 Oct 12. [PubMed:17932689 ]
  2. Colabufo NA, Berardi F, Cantore M, Perrone MG, Contino M, Inglese C, Niso M, Perrone R, Azzariti A, Simone GM, Porcelli L, Paradiso A: Small P-gp modulating molecules: SAR studies on tetrahydroisoquinoline derivatives. Bioorg Med Chem. 2008 Jan 1;16(1):362-73. Epub 2007 Sep 25. [PubMed:17936633 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials Not Available
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00281 mg/mLALOGPS
logP5.46ALOGPS
logP6.81ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)12.06ChemAxon
pKa (Strongest Basic)8.35ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area89.13 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity165.2 m3·mol-1ChemAxon
Polarizability63.43 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8334
Blood Brain Barrier+0.6042
Caco-2 permeable-0.5842
P-glycoprotein substrateSubstrate0.743
P-glycoprotein inhibitor IInhibitor0.9227
P-glycoprotein inhibitor IIInhibitor0.982
Renal organic cation transporterNon-inhibitor0.7088
CYP450 2C9 substrateNon-substrate0.7961
CYP450 2D6 substrateNon-substrate0.7668
CYP450 3A4 substrateSubstrate0.7789
CYP450 1A2 substrateNon-inhibitor0.8964
CYP450 2C9 inhibitorNon-inhibitor0.6245
CYP450 2D6 inhibitorNon-inhibitor0.9594
CYP450 2C19 inhibitorNon-inhibitor0.872
CYP450 3A4 inhibitorInhibitor0.6329
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7027
Ames testNon AMES toxic0.649
CarcinogenicityNon-carcinogens0.9279
BiodegradationNot ready biodegradable0.9946
Rat acute toxicity2.3993 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8558
hERG inhibition (predictor II)Inhibitor0.9543
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as acridones. These are acridines containing a ketone group attached to the C9 carbon atom of the acridine moiety.
KingdomChemical entities
Super ClassOrganic compounds
ClassOrganoheterocyclic compounds
Sub ClassQuinolines and derivatives
Direct ParentAcridones
Alternative ParentsAromatic anilides / Quinoline carboxamides / Hydroquinolones / Hydroquinolines / Tetrahydroisoquinolines / Phenethylamines / Anisoles / Alkyl aryl ethers / Aralkylamines / Pyridines and derivatives
SubstituentsAcridone / Aromatic anilide / Quinoline-8-carboxamide / Dihydroquinolone / Dihydroquinoline / Tetrahydroisoquinoline / Phenethylamine / Anisole / Alkyl aryl ether / Aralkylamine
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Uniprot Name:
Multidrug resistance protein 1
Molecular Weight:
141477.255 Da
References
  1. Hubensack M, Muller C, Hocherl P, Fellner S, Spruss T, Bernhardt G, Buschauer A: Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. J Cancer Res Clin Oncol. 2008 May;134(5):597-607. Epub 2007 Oct 12. [PubMed:17932689 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Uniprot Name:
ATP-binding cassette sub-family G member 2
Molecular Weight:
72313.47 Da
References
  1. Karla PK, Earla R, Boddu SH, Johnston TP, Pal D, Mitra A: Molecular expression and functional evidence of a drug efflux pump (BCRP) in human corneal epithelial cells. Curr Eye Res. 2009 Jan;34(1):1-9. doi: 10.1080/02713680802518251. [PubMed:19172464 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:
SLCO1B1
Uniprot ID:
Q9Y6L6
Uniprot Name:
Solute carrier organic anion transporter family member 1B1
Molecular Weight:
76447.99 Da
References
  1. Oostendorp RL, van de Steeg E, van der Kruijssen CM, Beijnen JH, Kenworthy KE, Schinkel AH, Schellens JH: Organic anion-transporting polypeptide 1B1 mediates transport of Gimatecan and BNP1350 and can be inhibited by several classic ATP-binding cassette (ABC) B1 and/or ABCG2 inhibitors. Drug Metab Dispos. 2009 Apr;37(4):917-23. doi: 10.1124/dmd.108.024901. Epub 2009 Jan 12. [PubMed:19139163 ]
Drug created on October 20, 2007 14:07 / Updated on September 01, 2017 11:22