Identification

Name
Elacridar
Accession Number
DB04881
Type
Small Molecule
Groups
Investigational
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
Synonyms
Not Available
External IDs
LY-335979 / LY335979
Product Ingredients
IngredientUNIICASInChI Key
Elacridar hydrochlorideNX2BHH1A5B143851-98-3IQOJZZHRYSSFJM-UHFFFAOYSA-N
Categories
UNII
N488540F94
CAS number
143664-11-3
Weight
Average: 563.6429
Monoisotopic: 563.242021181
Chemical Formula
C34H33N3O5
InChI Key
OSFCMRGOZNQUSW-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.

TargetActionsOrganism
UMultidrug resistance protein 1Not AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not 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 Interactions
Not Available

References

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
KEGG Drug
D03968
PubChem Compound
119373
PubChem Substance
175426884
ChemSpider
106620
BindingDB
50206310
ChEMBL
CHEMBL396298

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not 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
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as acridones. These are acridines containing a ketone group attached to the C9 carbon atom of the acridine moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Benzoquinolines
Direct Parent
Acridones
Alternative Parents
Aromatic anilides / Quinoline carboxamides / Hydroquinolones / Hydroquinolines / Tetrahydroisoquinolines / Phenethylamines / Anisoles / Alkyl aryl ethers / Aralkylamines / Pyridines and derivatives
show 9 more
Substituents
Acridone / Aromatic anilide / Quinoline-8-carboxamide / Dihydroquinolone / Dihydroquinoline / Tetrahydroisoquinoline / Phenethylamine / Anisole / Alkyl aryl ether / Aralkylamine
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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 fro...
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, prostagland...
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 November 09, 2017 03:48