This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Name
Zosuquidar
Accession Number
DB06191
Type
Small Molecule
Groups
Investigational
Description

Zosuquidar is a compound of antineoplastic drug candidates currently under development. It is now in "Phase 3" of clinical tests in the United States. Its action mechanism consists of the inhibition of P-glycoproteins; other drugs with this mechanism include tariquidar and laniquidar.

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Zosuquidar trihydrochloride813AGY3126167465-36-3ZPFVQKPWGDRLHL-WITOOOCMSA-N
Categories
UNII
AB5K82X98Y
CAS number
167354-41-8
Weight
Average: 527.616
Monoisotopic: 527.238433576
Chemical Formula
C32H31F2N3O2
InChI Key
IHOVFYSQUDPMCN-DBEBIPAYSA-N
InChI
InChI=1S/C32H31F2N3O2/c33-32(34)29-22-7-1-3-9-24(22)31(25-10-4-2-8-23(25)30(29)32)37-17-15-36(16-18-37)19-21(38)20-39-28-13-5-12-27-26(28)11-6-14-35-27/h1-14,21,29-31,38H,15-20H2/t21-,29-,30+,31-/m1/s1
IUPAC Name
(2R)-1-{4-[(2R,4S)-3,3-difluorotetracyclo[10.4.0.0²,⁴.0⁵,¹⁰]hexadeca-1(16),5,7,9,12,14-hexaen-11-yl]piperazin-1-yl}-3-(quinolin-5-yloxy)propan-2-ol trihydrochloride
SMILES
[H][C@]12C3=CC=CC=C3[C@H](N3CCN(C[C@@H](O)COC4=CC=CC5=C4C=CC=N5)CC3)C3=CC=CC=C3[C@@]1([H])C2(F)F

Pharmacology

Indication

Investigated for use/treatment in leukemia (myeloid) and myelodysplastic syndrome.

Pharmacodynamics
Not Available
Mechanism of action

P-glycoproteins are proteins which convert the energy derived from the hydrolysis of ATP to structural changes in protein molecules, in order to perform coupling, thus discharging medicine from cells. If P-glycoprotein coded with the MDR1 gene manifests itself in cancer cells, it discharges much of the antineoplastic drugs from the cells, making cancer cells medicine tolerant, and rendering antineoplastic drugs ineffective. This protein also manifests itself in normal organs not affected by the cancer (such as the liver, small intestine, and skin cells in blood vessels of the brain), and participates in the transportation of medicine. The compound Zosuquidar inhibits this P-glycoprotein, causing the cancer cells to lose their medicine tolerance, and making antineoplastic drugs effective.

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
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Zosuquidar.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Zosuquidar.
AmitriptylineThe serum concentration of Amitriptyline can be increased when it is combined with Zosuquidar.
Ascorbic acidThe serum concentration of Ascorbic acid can be increased when it is combined with Zosuquidar.
BenzylpenicillinThe excretion of Benzylpenicillin can be decreased when combined with Zosuquidar.
BetamethasoneThe serum concentration of Betamethasone can be increased when it is combined with Zosuquidar.
CarbamazepineThe serum concentration of Carbamazepine can be increased when it is combined with Zosuquidar.
ChlorambucilThe serum concentration of Chlorambucil can be increased when it is combined with Zosuquidar.
ChlorpromazineThe serum concentration of Chlorpromazine can be increased when it is combined with Zosuquidar.
CimetidineThe serum concentration of Cimetidine can be increased when it is combined with Zosuquidar.
Food Interactions
Not Available

References

General References
Not Available
External Links
PubChem Compound
153997
ChemSpider
24599682
BindingDB
50420186
ChEMBL
CHEMBL444172
HET
ZQU
Wikipedia
Zosuquidar
PDB Entries
6fn1

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentMyeloid Leukemias2
3CompletedTreatmentLeukemias / Myelodysplastic Syndromes1

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
logP4.82ChemAxon
pKa (Strongest Acidic)14.08ChemAxon
pKa (Strongest Basic)7.97ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area48.83 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity146.68 m3·mol-1ChemAxon
Polarizability56.3 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8998
Blood Brain Barrier+0.9118
Caco-2 permeable-0.6096
P-glycoprotein substrateSubstrate0.8405
P-glycoprotein inhibitor IInhibitor0.8163
P-glycoprotein inhibitor IIInhibitor0.9785
Renal organic cation transporterNon-inhibitor0.51
CYP450 2C9 substrateNon-substrate0.7839
CYP450 2D6 substrateNon-substrate0.6365
CYP450 3A4 substrateSubstrate0.5488
CYP450 1A2 substrateInhibitor0.6444
CYP450 2C9 inhibitorNon-inhibitor0.6474
CYP450 2D6 inhibitorInhibitor0.5249
CYP450 2C19 inhibitorNon-inhibitor0.6238
CYP450 3A4 inhibitorNon-inhibitor0.7309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7929
Ames testNon AMES toxic0.638
CarcinogenicityNon-carcinogens0.9009
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7076 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8796
hERG inhibition (predictor II)Inhibitor0.9373
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

Classification
Not classified

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. Nies AT, Herrmann E, Brom M, Keppler D: Vectorial transport of the plant alkaloid berberine by double-transfected cells expressing the human organic cation transporter 1 (OCT1, SLC22A1) and the efflux pump MDR1 P-glycoprotein (ABCB1). Naunyn Schmiedebergs Arch Pharmacol. 2008 Feb;376(6):449-61. Epub 2007 Dec 19. [PubMed:18157518]
  2. Luker GD, Pica CM, Kumar AS, Covey DF, Piwnica-Worms D: Effects of cholesterol and enantiomeric cholesterol on P-glycoprotein localization and function in low-density membrane domains. Biochemistry. 2000 Jul 4;39(26):7651-61. [PubMed:10869171]

Transporters

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 March 19, 2008 10:16 / Updated on September 07, 2018 03:30