EXISULIND

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H17FO4S
Molecular Weight	372.4118
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC/1=C(CC(=O)O)c2cc(ccc2\C1=C(\[H])/c3ccc(cc3)S(=O)(=O)C)F

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	372.4118
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

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 7728		112.0 µM [IC50]
Phosphodiesterase 4 50 Target ID: CHEMBL2093863 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11358813	Inhibitor 7728		116.0 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Colorectal cancer 94 Sources: https://clinicaltrials.gov/ct2/show/NCT00026468	Primary	Phase III 643	Unknown Approved Use Unknown
Small intestine cancer 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00026468	Primary	Phase III 643	Unknown Approved Use Unknown
Non-small cell lung cancer 195 Sources: https://clinicaltrials.gov/ct2/show/NCT00085826	Primary	Phase III 643	Unknown Approved Use Unknown
Prostate cancer 159 Sources: https://clinicaltrials.gov/ct2/show/NCT00078910	Primary	Phase II 1101	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 1467	inhibitor 1604	inhibitor 1702	inhibitor 1475

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYPs 21 CYP2E1 790 CYP19A1 56 CYP1A2 1383 NTCP 32 CYP2C19 1325 OATPs 1 CYP2A6 627 MRP2 346	CYPs 31 UGT1A1 393 UGT1A3 397 UGT1A9 357 UGT2B15 191 UGT2B7 362 UGT2B17 203 UGT1A4 330 UGT1A6 289 UGT1A7 221 UGT1A8 266 UGT1A10 273 UGT2B4 233	CYP1A1 98 UGT1A1 65 GSTP1 1 CYP1A2 637 NQO1 1 CYP1B1 47

Drug as perpetrator

Target	Modality	Activity
CYP3A4 1772	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=170466321	inconclusive [IC50 13.8029 uM]
CYP2C9 1648	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=170466321	inconclusive [IC50 34.6713 uM]
CYP2A6 659	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/625246#sid=160698611	no [IC50 >10 uM]
CYP2E1 871	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/625250#sid=160698611	no [IC50 >10 uM]
CYP19A1 56	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743139#sid=144207073	no
CYP2C19 1392	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/899#sid=11111778	no
CYP2C9 1648	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/883#sid=11111778	no
CYP2D6 1738	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/891#sid=11111778	no
CYPs 26	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/11772293/	no
CYP1A2 1532	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/410#sid=11111778	yes [IC50 12.6 uM]
CYP1A1 192	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
CYP1A2 1532	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
CYP1B1 63	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
GSTP1 1	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
MRP2 434	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
NQO1 1	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
NTCP 33	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
OATPs 1	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
UGT1A1 240	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes

Drug as victim

Target	Modality	Activity
UGT1A8 266	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	like
UGT1A10 273	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A4 330	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A6 289	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A7 221	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT2B4 233	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
CYPs 31	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/11772293/	no
UGT2B15 191	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	no
UGT2B17 203	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	no
UGT1A3 397	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 15 uM]
UGT2B7 362	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 34.1 uM]
UGT1A9 357	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 44.6 uM]
UGT1A1 393	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 5.2 uM]

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1507	inhibitor 1489 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
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
Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin.	2000 Jul 1	10910034
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
Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells.	2001 Nov	11602670
Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy.	2001 Sep	11490238
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
Exisulind and related compounds inhibit expression and function of the androgen receptor in human prostate cancer cells.	2003 Oct 15	14581372
Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid.	2004 Aug	15300575
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
Nobiletin, a citrus flavonoid, down-regulates matrix metalloproteinase-7 (matrilysin) expression in HT-29 human colorectal cancer cells.	2005 Feb	15725655
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
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
Sporadic adenomatous polyp regression with exisulind is effective but toxic: a randomised, double blind, placebo controlled, dose-response study.	2006 Mar	16150858
Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells.	2006 May	16731751
Gene expression profiling in R-flurbiprofen-treated prostate cancer: R-Flurbiprofen regulates prostate stem cell antigen through activation of AKT kinase.	2006 Nov 15	16949054
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
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	18059344
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.

Substance Class	Chemical Created by `admin` on `Sat Jun 26 07:49:26 UTC 2021` Edited by `admin` on `Sat Jun 26 07:49:26 UTC 2021`
Record UNII	K619IIG2R9
Record Status	`Validated (UNII)`
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Name

Type

Language

EXISULIND

Official Name

English

SULINDAC RELATED COMPOUND B [USP]

Common Name

English

5-FLUORO-2-METHYL-1-((Z)-P-(METHYLSULFONYL)BENZYLIDENE)INDENE-3-ACETIC ACID

Common Name

English

SULINDAC RELATED COMPOUND B

Common Name

English

1H-INDENE-3-ACETIC ACID, 5-FLUORO-2-METHYL-1-((4-(METHYLSULFONYL)PHENYL)METHYLENE)-, (1Z)-

Systematic Name

English

SULINDAC SULFONE

Common Name

English

APTOSYN

Brand Name

English

SULINDAC RELATED COMPOUND B [USP-RS]

Common Name

English

EXISULIND [WHO-DD]

Common Name

English

EXISULIND [MI]

Common Name

English

PREVATEC

Brand Name

English

SULINDAC SPECIFIED IMPURITY B [EP]

Common Name

English

EXISULIND [MART.]

Common Name

English

EXISULIND [INN]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/14/1387