Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C32H31F2N3O2.3ClH |
Molecular Weight | 636.987 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.Cl.Cl.[H][C@]12C3=CC=CC=C3[C@H](N4CCN(C[C@@H](O)COC5=CC=CC6=NC=CC=C56)CC4)C7=CC=CC=C7[C@@]1([H])C2(F)F
InChI
InChIKey=ZPFVQKPWGDRLHL-WITOOOCMSA-N
InChI=1S/C32H31F2N3O2.3ClH/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;3*1H/t21-,29-,30+,31-;;;/m1.../s1
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/8797588Curator's Comment: Description was created based on several sources, including
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8797588
Curator's Comment: Description was created based on several sources, including
Zosuquidar (LY-335979) is an experimental antineoplastic drug. It is is a potent modulator of P-glycoprotein-mediated multi-drug resistance with Ki of 60 nM. Zosuqidar was initially characterized by Syntex Corporation, which was acquired by Roche in 1990. Roche licensed the drug to Eli Lilly in 1997. It was granted orphan drug status by the FDA in 2006 for AML. Zosuquidar Trihydrochloride had been in phase III clinical trials by Kanisa Pharmaceuticals for the treatment of acute myeloid leukaemia. However, this research has been discontinued.
Originator
Sources: http://adisinsight.springer.com/drugs/800005159
Curator's Comment: Zosuquidar was originally discovered and identified as an MDR modulator by Syntex Corporation. Syntex was acquired by Roche in 1990. # Syntex Corporation (Roche)
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL4302 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8797588 |
60.0 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
0.31 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15809877 |
300 mg/m² 2 times / day multiple, oral dose: 300 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: VINORELBINE |
ZOSUQUIDAR plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1111 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15809877 |
300 mg/m² 2 times / day multiple, oral dose: 300 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: VINORELBINE |
ZOSUQUIDAR plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
16.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15809877 |
300 mg/m² 2 times / day multiple, oral dose: 300 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: VINORELBINE |
ZOSUQUIDAR plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
Doses
Dose | Population | Adverse events |
---|---|---|
300 mg/m2 2 times / day multiple, oral MTD Dose: 300 mg/m2, 2 times / day Route: oral Route: multiple Dose: 300 mg/m2, 2 times / day Co-administed with:: vinorelbine(22.5 mg/m2 IV weekly for 3 weeks every 28 days) Sources: Page: p.157, 158 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: Page: p.157, 158 |
DLT: febrile neutropeni... Other AEs: Stomatitis, Neutropenia... Dose limiting toxicities: febrile neutropeni (grade 4, 33.3%) Other AEs:Stomatitis (grade 3) Sources: Page: p.157, 158Neutropenia (grade 3) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Neutropenia | grade 3 | 300 mg/m2 2 times / day multiple, oral MTD Dose: 300 mg/m2, 2 times / day Route: oral Route: multiple Dose: 300 mg/m2, 2 times / day Co-administed with:: vinorelbine(22.5 mg/m2 IV weekly for 3 weeks every 28 days) Sources: Page: p.157, 158 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: Page: p.157, 158 |
Stomatitis | grade 3 | 300 mg/m2 2 times / day multiple, oral MTD Dose: 300 mg/m2, 2 times / day Route: oral Route: multiple Dose: 300 mg/m2, 2 times / day Co-administed with:: vinorelbine(22.5 mg/m2 IV weekly for 3 weeks every 28 days) Sources: Page: p.157, 158 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: Page: p.157, 158 |
febrile neutropeni | grade 4, 33.3% DLT |
300 mg/m2 2 times / day multiple, oral MTD Dose: 300 mg/m2, 2 times / day Route: oral Route: multiple Dose: 300 mg/m2, 2 times / day Co-administed with:: vinorelbine(22.5 mg/m2 IV weekly for 3 weeks every 28 days) Sources: Page: p.157, 158 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: Page: p.157, 158 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
likely [Inhibition 50 uM] | ||||
no | ||||
no | ||||
no | ||||
yes [IC50 10.684 uM] | ||||
yes [Ki 12.3 uM] | ||||
yes [Ki 25.3 uM] | ||||
yes [Ki 3.8 uM] | ||||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
likely |
PubMed
Title | Date | PubMed |
---|---|---|
Bioanalysis of zosuquidar trihydrochloride (LY335979) in small volumes of human and murine plasma by ion-pairing reversed-phase high-performance liquid chromatography. | 2003 Dec 5 |
|
A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy. | 2004 May 15 |
|
Phase I study of docetaxel in combination with the P-glycoprotein inhibitor, zosuquidar, in resistant malignancies. | 2004 Nov 1 |
|
Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats. | 2006 Apr |
|
Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood-brain barrier. | 2007 Sep |
|
Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelfinavir into the brain but not into the cerebrospinal fluid. | 2007 Sep |
|
Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar. | 2007 Sep |
|
Gateways to clinical trials. | 2008 Apr |
|
Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML). | 2008 Feb 13 |
|
ABC transporters and the accumulation of imatinib and its active metabolite CGP74588 in rat C6 glioma cells. | 2008 Mar |
|
Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors. | 2008 Mar 11 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT00046930
Zosuquidar 550 mg/day by continuous intravenous infusion through a central venous catheter over approximately 6 hours on days 1, 2, and 3.
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8797588
Zosuquidar (LY-335979) alone shows the cytotoxicity to drug-sensitive and MDR cell lines with IC50 ranging from 6 uM-16 uM and produces its ability to completely reverse the resistance of the oncolytics (vinblastine, doxorubicin, or etoposide) to the MDR cell lines P388/ADR, MCF7/ADR, 2780AD, or UCLA-P3.003VLB at concentration of 0.1 and 0.5 uM
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Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C1744
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EU-Orphan Drug |
EU/3/06/355
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FDA ORPHAN DRUG |
212805
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167465-36-3
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C2225
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KK-112
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100000177257
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C095179
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m11666
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DBSALT000558
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CHEMBL444172
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813AGY3126
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DTXSID1057662
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725086
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ACTIVE MOIETY
SUBSTANCE RECORD