Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C32H31F2N3O2 |
Molecular Weight | 527.6042 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
[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=IHOVFYSQUDPMCN-DBEBIPAYSA-N
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
Molecular Formula | C32H31F2N3O2 |
Molecular Weight | 527.6042 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
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 |
---|---|---|
Potential for improvement of docetaxel-based chemotherapy: a pharmacological review. | 2005 Jul 25 |
|
Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats. | 2006 Apr |
|
Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar. | 2007 Sep |
|
Resistance to chemotherapy: new treatments and novel insights into an old problem. | 2008 Aug 5 |
|
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. | 2009 Apr |
|
Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice. | 2009 Jul 10 |
|
Leukemic blast and natural killer cell P-glycoprotein function and inhibition in a clinical trial of zosuquidar infusion in acute myeloid leukemia. | 2009 Jun |
|
P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients. | 2009 Jun 23 |
|
A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen. | 2009 Sep |
|
Challenges in treating older patients with acute myeloid leukemia. | 2010 |
|
Gateways to clinical trials. | 2010 Jan-Feb |
|
Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. | 2010 Nov 18 |
|
PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line. | 2010 Sep |
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
Substance Class |
Chemical
Created
by
admin
on
Edited
Fri Dec 15 16:26:33 GMT 2023
by
admin
on
Fri Dec 15 16:26:33 GMT 2023
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Record UNII |
AB5K82X98Y
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Record Status |
Validated (UNII)
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Record Version |
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NCI_THESAURUS |
C1744
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AB5K82X98Y
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DTXSID9057894
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100000177268
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m11666
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CHEMBL444172
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DB06191
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ZOSUQUIDAR
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8083
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C76198
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167354-41-8
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TARGET -> INHIBITOR |
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ACTIVE MOIETY |
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