EXISULIND

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 Search

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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11358813 | https://www.ncbi.nlm.nih.gov/pubmed/11249724 | https://www.ncbi.nlm.nih.gov/pubmed/15230629

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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Phosphodiesterase 5A 30 Target ID: CHEMBL1827 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11358813	Inhibitor 8297		112.0 µM [IC50]
Phosphodiesterase 4 52 Target ID: CHEMBL2093863 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11358813	Inhibitor 8297		116.0 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Colorectal cancer 101 Sources: https://clinicaltrials.gov/ct2/show/NCT00026468	Primary	Phase III 656	Unknown Approved Use Unknown
Small intestine cancer 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00026468	Primary	Phase III 656	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT00085826	Primary	Phase III 656	Unknown Approved Use Unknown
Prostate cancer 178 Sources: https://clinicaltrials.gov/ct2/show/NCT00078910	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
9.85 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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

Value	Dose	Analyte	Population
48.7 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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

T_1/2

Value	Dose	Analyte	Population
4.88 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10656435	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

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYPs 22 CYP2E1 882 CYP19A1 60 CYP1A2 1524 NTCP 34 CYP2C19 1478 OATPs 1 CYP2A6 707 MRP2 383	CYPs 33 UGT1A1 418 UGT1A3 422 UGT1A9 380 UGT2B15 203 UGT2B7 389 UGT2B17 213 UGT1A4 347 UGT1A6 307 UGT1A7 236 UGT1A8 283 UGT1A10 291 UGT2B4 249	CYP1A1 108 UGT1A1 69 GSTP1 1 CYP1A2 701 NQO1 1 CYP1B1 51

Drug as perpetrator

Target	Modality	Activity
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=170466321	inconclusive [IC50 13.8029 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=170466321	inconclusive [IC50 34.6713 uM]
CYP2A6 739	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/625246#sid=160698611	no [IC50 >10 uM]
CYP2E1 970	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/625250#sid=160698611	no [IC50 >10 uM]
CYP19A1 60	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743139#sid=144207073	no
CYP2C19 1553	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/899#sid=11111778	no
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/883#sid=11111778	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/891#sid=11111778	no
CYPs 28	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/11772293/	no
CYP1A2 1692	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/410#sid=11111778	yes [IC50 12.6 uM]
CYP1A1 218	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
CYP1A2 1692	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
CYP1B1 67	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
GSTP1 1	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
MRP2 475	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
NQO1 1	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
NTCP 35	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
OATPs 1	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
UGT1A1 254	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes

Drug as victim

Target	Modality	Activity
UGT1A8 283	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	like
UGT1A10 291	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A4 347	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A6 307	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A7 236	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT2B4 249	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
CYPs 33	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11772293/	no
UGT2B15 203	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	no
UGT2B17 213	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	no
UGT1A3 422	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 15 uM]
UGT2B7 389	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 34.1 uM]
UGT1A9 380	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 44.6 uM]
UGT1A1 418	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 5.2 uM]

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/588834#sid=50107023

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00E9KK	https://www.1pchem.com/search?query=1P00E9KK
1PlusChem LLC	1P00ECHB	https://www.1pchem.com/search?query=1P00ECHB
Alfa Chemistry	189139	http://www.alfa-chemistry.com/search.aspx?q=189139
Alfa Chemistry	ACM59973807	http://www.alfa-chemistry.com/search.aspx?q=ACM59973807
Angene	AGN-PC-0SU6WN	http://www.angenechemical.com/productshow/AGN-PC-0SU6WN.html
Matrix Scientific	121209	http://www.matrixscientific.com/121209.html
MolPort	MolPort-003-850-357	https://www.molport.com/shop/molecule-link/MolPort-003-850-357
MuseChem	R002174	https://www.musechem.com/product/R002174.html
Toronto Research Chemicals	S699225	https://www.trc-canada.com/product-detail/?CatNum=S699225
Toronto Research Chemicals	S699323	https://www.trc-canada.com/product-detail/?CatNum=S699323
eMolecules	1934876	https://orderbb.emolecules.com/search/#?query=1934876
eMolecules	26751332	https://orderbb.emolecules.com/search/#?query=26751332
eMolecules	300088841	https://orderbb.emolecules.com/search/#?query=300088841
eNovation Chemicals	D759265	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D759265&searchbtn.x=0&searchbtn.y=0

PubMed

Title	Date	PubMed










Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process.	1999 Jul 15	10416599
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	11197048
Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells.	2000 Dec 1	11118042
Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation.	2000 Feb	10666051
Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1.	2000 Oct	11051267
Sulindac-associated choledocholithiasis.	2001 Jul	11467685
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	11375891
Sulindac sulfide-induced apoptosis involves death receptor 5 and the caspase 8-dependent pathway in human colon and prostate cancer cells.	2001 Sep 15	11559570
PPARgamma-mediated antineoplastic effect of NSAID sulindac on human oral squamous carcinoma cells.	2002 Apr 20	11948457
GATA-6 transcriptional regulation of 15-lipoxygenase-1 during NSAID-induced apoptosis in colorectal cancer cells.	2002 Feb 15	11861401
Exisulind in combination with docetaxel inhibits growth and metastasis of human lung cancer and prolongs survival in athymic nude rats with orthotopic lung tumors.	2002 Mar	11895925
Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation.	2002 Nov 1	12392815
Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells.	2003 Sep	14555707
Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid.	2004 Aug	15300575
Effect of nonsteroidal anti-inflammatory drugs on beta-catenin protein levels and catenin-related transcription in human colorectal cancer cells.	2004 Jul 5	15188006
Regression of mouse prostatic intraepithelial neoplasia by nonsteroidal anti-inflammatory drugs in the transgenic adenocarcinoma mouse prostate model.	2004 Nov 15	15570007
Inhibition of extracellular-signal regulated kinases 1/2 is required for apoptosis of human colon cancer cells in vitro by sulindac metabolites.	2004 Nov 15	15548677
Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer.	2005 Feb	15713900
Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes.	2005 Jul	15843492
The nonsteroidal anti-inflammatory drug Exisulind selectively induces apoptosis via JNK in secondary acute myeloid leukemia after myelodysplastic syndrome.	2005 Jun	15970671
A phase I/II dose-escalation study of exisulind and docetaxel in patients with hormone-refractory prostate cancer.	2005 May	15839914
Activation of protein kinase G up-regulates expression of 15-lipoxygenase-1 in human colon cancer cells.	2005 Sep 15	16166323
Induction of spermidine/spermine N1-acetyltransferase (SSAT) by aspirin in Caco-2 colon cancer cells.	2006 Feb 15	16262603
Sulindac sulfide and exisulind inhibit expression of the estrogen and progesterone receptors in human breast cancer cells.	2006 Jun 1	16740773
Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells.	2006 May	16731751
Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon.	2007 Apr 1	17409426
Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence.	2007 Oct 1	17908994
Malignant transformation of normal enterocytes following downregulation of Bak expression.	2008	18349538
A comparison of the effectiveness of selected non-steroidal anti-inflammatory drugs and their derivatives against cancer cells in vitro.	2008 Feb	17447067
Activation of protein kinase G Increases the expression of p21CIP1, p27KIP1, and histidine triad protein 1 through Sp1.	2008 Jul 1	18593937
Sulindac and its metabolites induce carcinogen metabolizing enzymes in human colon cancer cells.	2008 Mar 1	17985343
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	18758305
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	19501039
Sulindac metabolites induce proteosomal and lysosomal degradation of the epidermal growth factor receptor.	2010 Apr	20332299
Structural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10.	2015 Jun 5	25532697

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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.

Name

Type

Language

EXISULIND

Official Name

English

FGN-1

Code

English

SULINDAC RELATED COMPOUND B

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