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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
Structure of ZOSUQUIDAR TRIHYDROCHLORIDE

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

HIDE SMILES / InChI
Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE
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

Description
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

Syntex
47
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

Unknown
139594
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8297
 60.0 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase III
656
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
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
VINORELBINE
 ZOSUQUIDAR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
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
VINORELBINE
 ZOSUQUIDAR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
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
VINORELBINE
 ZOSUQUIDAR plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FASTED
Doses

Doses

DosePopulationAdverse 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:
https://pubmed.ncbi.nlm.nih.gov/15809877
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:
https://pubmed.ncbi.nlm.nih.gov/15809877
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)
Neutropenia (grade 3)
Sources:
https://pubmed.ncbi.nlm.nih.gov/15809877
Page: p.157, 158
AEs

AEs

AESignificanceDosePopulation
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:
https://pubmed.ncbi.nlm.nih.gov/15809877
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:
https://pubmed.ncbi.nlm.nih.gov/15809877
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:
https://pubmed.ncbi.nlm.nih.gov/15809877
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:
https://pubmed.ncbi.nlm.nih.gov/15809877
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:
https://pubmed.ncbi.nlm.nih.gov/15809877
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:
https://pubmed.ncbi.nlm.nih.gov/15809877
Page: p.157, 158
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
inhibitor
1587
inhibitor
1767
inhibitor
1852

OverviewOther

Other InhibitorOther SubstrateOther Inducer
CYP2B6
810

MRP1
106

BCRP
699

CYP1A2
1524

P-gp
1461

MRP2
383
CYP3A
191
Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
CYP1A2
1692
 likely [Inhibition 50 uM]
BCRP
773
 no
MRP1
172
 no
MRP2
475
 no
CYP2D6
1891
 yes [IC50 10.684 uM]
CYP2C9
1819
 yes [Ki 12.3 uM]
CYP2B6
1001
 yes [Ki 25.3 uM]
CYP3A4
1925
 yes [Ki 3.8 uM]
P-gp
1650
 yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
CYP3A
191
 likely
PubMed

PubMed

TitleDatePubMed
Gateways to clinical trials.
2008 Apr
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
A phase I trial of continuous infusion of the multidrug resistance inhibitor zosuquidar with daunorubicin and cytarabine in acute myeloid leukemia.
2009 Aug
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

Patents

20040097519
2
20050106182
2
20060046967
5

Sample Use Guides

In Vivo Use Guide
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
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 Fri Dec 15 15:46:07 GMT 2023
Edited
by admin
on Fri Dec 15 15:46:07 GMT 2023
Record UNII
813AGY3126
Record Status Validated (UNII)
Record Version
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Name Type Language
ZOSUQUIDAR TRIHYDROCHLORIDE
MI   USAN   WHO-DD  
USAN  
Official Name English
NSC-725086
Code English
Zosuquidar trihydrochloride [WHO-DD]
Common Name English
(R)-4-[(1aR,6R,10bS)-1,2-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,E]cyclopropa[c]cycloheptan-6-yl]-α-[(5-quinoloyloxy)methyl]-1-piperazineethanol trihydrochloride
Systematic Name English
ZOSUQUIDAR TRIHYDROCHLORIDE [USAN]
Common Name English
ZOSUQUIDAR TRIHYDROCHLORIDE [MI]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C1744
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
EU-Orphan Drug EU/3/06/355
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
FDA ORPHAN DRUG 212805
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
Code System Code Type Description
CAS
167465-36-3
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
NCI_THESAURUS
C2225
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
USAN
KK-112
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
SMS_ID
100000177257
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
MESH
C095179
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
MERCK INDEX
m11666
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY Merck Index
DRUG BANK
DBSALT000558
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
ChEMBL
CHEMBL444172
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
FDA UNII
813AGY3126
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
EPA CompTox
DTXSID1057662
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
NSC
725086
Created by admin on Fri Dec 15 15:46:07 GMT 2023 , Edited by admin on Fri Dec 15 15:46:07 GMT 2023
PRIMARY
Related Record Type Details
Structure of ZOSUQUIDAR
PARENT -> SALT/SOLVATE
Related Record Type Details
Structure of ZOSUQUIDAR
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