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Details

Stereochemistry ACHIRAL
Molecular Formula C20H17FO4S
Molecular Weight 372.41
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of EXISULIND

SMILES

CC1=C(CC(O)=O)C2=C(C=CC(F)=C2)\C1=C/C3=CC=C(C=C3)S(C)(=O)=O

InChI

InChIKey=MVGSNCBCUWPVDA-MFOYZWKCSA-N
InChI=1S/C20H17FO4S/c1-12-17(9-13-3-6-15(7-4-13)26(2,24)25)16-8-5-14(21)10-19(16)18(12)11-20(22)23/h3-10H,11H2,1-2H3,(H,22,23)/b17-9-

HIDE SMILES / InChI

Molecular Formula C20H17FO4S
Molecular Weight 372.41
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Exisulind (tentative trade name Aptosyn) is an antineoplastic agent, which was originally developed by Cell Pathways. This drug is an inhibitor of phosphodiesterase (PDE) isozymes: PDE5 and PDE4. Inhibition of PDE5 appears to be pharmacologically relevant, which leads to increase cGMP and activate protein kinase G at doses that induce apoptosis, whereas cyclic AMP levels were not changed. Exisulind has been in phase III clinical trials for the treatment of Non-Small Cell Lung Cancer and for the treatment of polyps in patients who have familial adenomatous polyposis (Colorectal Cancer and Small Intestine Cancer). In addition, this drug was in phase II/III for the treatment of Prostate Cancer, however, there studies have been discontinued.

Originator

Curator's Comment: compounds were originally developed by Cell Pathways, which was acquired by, and integrated into, OSI Pharmaceuticals in June 2003.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
112.0 µM [IC50]
116.0 µM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
9.85 mg/L
400 mg 2 times / day single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
18.2 μM
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
48.1 μM
400 mg 2 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
48.7 mg × h/L
400 mg 2 times / day single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
127 μM × h
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
174 μM × h
400 mg 2 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
4.88 h
400 mg 2 times / day single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
6.03 h
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
10.9 h
400 mg 2 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
EXISULIND plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
inconclusive [IC50 13.8029 uM]
inconclusive [IC50 34.6713 uM]
no [IC50 >10 uM]
no [IC50 >10 uM]
no
no
no
no
no
yes [IC50 12.6 uM]
yes
yes
yes
yes
yes
yes
yes
yes
yes
Drug as victimTox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Non-steroidal anti-inflammatory drugs with different cyclooxygenase inhibitory profiles that prevent aberrant crypt foci formation but vary in acute gastrotoxicity in a rat model.
2000 Dec
Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells.
2000 Dec 1
Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1.
2000 Oct
Sulindac-associated choledocholithiasis.
2001 Jul
Rat colorectal tumours treated with a range of non-steroidal anti-inflammatory drugs show altered cyclooxygenase-2 and cyclooxygenase-1 splice variant mRNA expression levels.
2001 Jun
Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK1.
2001 May 11
Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy.
2001 Sep
Sulindac sulfide-induced apoptosis involves death receptor 5 and the caspase 8-dependent pathway in human colon and prostate cancer cells.
2001 Sep 15
PPARgamma-mediated antineoplastic effect of NSAID sulindac on human oral squamous carcinoma cells.
2002 Apr 20
GATA-6 transcriptional regulation of 15-lipoxygenase-1 during NSAID-induced apoptosis in colorectal cancer cells.
2002 Feb 15
Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation.
2002 Nov 1
Exisulind and related compounds inhibit expression and function of the androgen receptor in human prostate cancer cells.
2003 Oct 15
Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells.
2003 Sep
Effect of nonsteroidal anti-inflammatory drugs on beta-catenin protein levels and catenin-related transcription in human colorectal cancer cells.
2004 Jul 5
Regression of mouse prostatic intraepithelial neoplasia by nonsteroidal anti-inflammatory drugs in the transgenic adenocarcinoma mouse prostate model.
2004 Nov 15
Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes.
2005 Jul
The nonsteroidal anti-inflammatory drug Exisulind selectively induces apoptosis via JNK in secondary acute myeloid leukemia after myelodysplastic syndrome.
2005 Jun
A phase I/II dose-escalation study of exisulind and docetaxel in patients with hormone-refractory prostate cancer.
2005 May
Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells.
2006 May
The proapoptotic effects of sulindac, sulindac sulfone and indomethacin are mediated by nucleolar translocation of the RelA(p65) subunit of NF-kappaB.
2008 Apr 17
A comparison of the effectiveness of selected non-steroidal anti-inflammatory drugs and their derivatives against cancer cells in vitro.
2008 Feb
Sulindac and its metabolites induce carcinogen metabolizing enzymes in human colon cancer cells.
2008 Mar 1
Phase I/II study of vinorelbine and exisulind as first-line treatment of advanced non-small cell lung cancer in patients at least 70 years old: a wisconsin oncology network study.
2008 Sep
15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is up-regulated by flurbiprofen and other non-steroidal anti-inflammatory drugs in human colon cancer HT29 cells.
2009 Jul 15
Sulindac metabolites induce proteosomal and lysosomal degradation of the epidermal growth factor receptor.
2010 Apr
Structural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10.
2015 Jun 5
Patents

Patents

Sample Use Guides

patients with androgen independent prostate carcinoma: receive weekly docetaxel for 4 weeks, followed by 2 weeks of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously.
Route of Administration: Oral
The effects of arsenic trioxide (ATO) in combination with sulindac (SUL), sulindac sulfide (SS) or sulindac sulfone (SF) on human (Jurkat, HL-60, K562 and HPB-ALL) and mouse (EL-4) leukemic cell lines were investigated. The combination of ATO (1 μM) with SS or SF at concentrations over 50 μM induced considerable cytotoxicity in all cell lines. Normal human lymphocytes exposed for 48 h to the combinations showed smaller decrease in viability. The mitochondrial membrane potential measurements (JC-1 probe) indicated an active involvement of mitochondria in the process. The results did not indicate involvement of an inhibitory effect of the combinations on NF-κB activity in Jurkat, HL-60 and K562 cells.
Substance Class Chemical
Created
by admin
on Sat Dec 16 18:03:11 GMT 2023
Edited
by admin
on Sat Dec 16 18:03:11 GMT 2023
Record UNII
K619IIG2R9
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
EXISULIND
INN   USAN  
Official Name English
FGN-1
Code English
SULINDAC RELATED COMPOUND B
USP-RS  
Common Name English
SULINDAC IMPURITY B [EP IMPURITY]
Common Name English
1H-Indene-3-acetic acid, 5-fluoro-2-methyl-1-[[4-(methylsulfonyl)phenyl]methylene]-, (1Z)-
Systematic Name English
SULINDAC RELATED COMPOUND B [USP IMPURITY]
Common Name English
SULINDAC SULFONE
Common Name English
APTOSYN
Brand Name English
SULINDAC RELATED COMPOUND B [USP-RS]
Common Name English
EXISULIND [USAN]
Common Name English
Exisulind [WHO-DD]
Common Name English
EXISULIND [MI]
Common Name English
5-Fluoro-2-methyl-1-[[4-(methylsulfonyl)phenyl]methylene]-1H-indene-3-acetic acid
Systematic Name English
PREVATEC
Brand Name English
EXISULIND [MART.]
Common Name English
SULINDAC SULPHONE
Common Name English
exisulind [INN]
Common Name English
Classification Tree Code System Code
EU-Orphan Drug EU/3/14/1387
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
NCI_THESAURUS C1323
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
FDA ORPHAN DRUG 79293
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
Code System Code Type Description
DRUG CENTRAL
3219
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
ChEMBL
CHEMBL488025
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
CHEBI
64212
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
USAN
II-79
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
MERCK INDEX
m5226
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY Merck Index
CAS
59864-04-9
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
NON-SPECIFIC STEREOCHEMISTRY
DRUG BANK
DB06246
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
PUBCHEM
5472495
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
NCI_THESAURUS
C1239
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
CAS
59973-80-7
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
INN
7744
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
RS_ITEM_NUM
1642020
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
EPA CompTox
DTXSID6040246
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
WIKIPEDIA
EXISULIND
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
FDA UNII
K619IIG2R9
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
MESH
C025463
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
SMS_ID
100000177152
Created by admin on Sat Dec 16 18:03:11 GMT 2023 , Edited by admin on Sat Dec 16 18:03:11 GMT 2023
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
Inhibits the enzyme cGMP-PDE, overexpressed in precancerous and cancerous colorectal cells, and induces apoptosis in such cells with minimal effects on normal cells.
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PARENT -> METABOLITE
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PARENT -> IMPURITY
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PARENT -> IMPURITY
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ACTIVE MOIETY