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

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

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 8146		112.0 µM [IC50]
Phosphodiesterase 4 52 Target ID: CHEMBL2093863 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11358813	Inhibitor 8146		116.0 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Colorectal cancer 97 Sources: https://clinicaltrials.gov/ct2/show/NCT00026468	Primary	Phase III 651	Unknown Approved Use Unknown
Small intestine cancer 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00026468	Primary	Phase III 651	Unknown Approved Use Unknown
Non-small cell lung cancer 197 Sources: https://clinicaltrials.gov/ct2/show/NCT00085826	Primary	Phase III 651	Unknown Approved Use Unknown
Prostate cancer 177 Sources: https://clinicaltrials.gov/ct2/show/NCT00078910	Primary	Phase II 1133	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 1532	inhibitor 1695	inhibitor 1789	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYPs 22 CYP2E1 846 CYP19A1 58 CYP1A2 1463 NTCP 33 CYP2C19 1410 OATPs 1 CYP2A6 670 MRP2 363	CYPs 32 UGT1A1 417 UGT1A3 421 UGT1A9 378 UGT2B15 202 UGT2B7 387 UGT2B17 212 UGT1A4 345 UGT1A6 306 UGT1A7 235 UGT1A8 282 UGT1A10 289 UGT2B4 248	CYP1A1 103 UGT1A1 66 GSTP1 1 CYP1A2 671 NQO1 1 CYP1B1 50

Drug as perpetrator

Target	Modality	Activity
CYP3A4 1857	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=170466321	inconclusive [IC50 13.8029 uM]
CYP2C9 1747	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=170466321	inconclusive [IC50 34.6713 uM]
CYP2A6 702	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/625246#sid=160698611	no [IC50 >10 uM]
CYP2E1 929	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/625250#sid=160698611	no [IC50 >10 uM]
CYP19A1 58	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743139#sid=144207073	no
CYP2C19 1484	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/899#sid=11111778	no
CYP2C9 1747	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/883#sid=11111778	no
CYP2D6 1826	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/891#sid=11111778	no
CYPs 28	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/11772293/	no
CYP1A2 1620	inhibitor 3185 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/410#sid=11111778	yes [IC50 12.6 uM]
CYP1A1 206	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
CYP1A2 1620	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
CYP1B1 66	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
GSTP1 1	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
MRP2 452	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
NQO1 1	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes
NTCP 34	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
OATPs 1	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/20430841/	yes
UGT1A1 249	inducer 1515 Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/	yes

Drug as victim

Target	Modality	Activity
UGT1A8 282	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	like
UGT1A10 289	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A4 345	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A6 306	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT1A7 235	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
UGT2B4 248	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	likely
CYPs 32	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/11772293/	no
UGT2B15 202	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	no
UGT2B17 212	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	no
UGT1A3 421	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 15 uM]
UGT2B7 387	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 34.1 uM]
UGT1A9 378	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 44.6 uM]
UGT1A1 417	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/15843492/	yes [Km 5.2 uM]

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1603	inhibitor 1584 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
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
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
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
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
Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells.	2003 Sep	14555707
Effect of nonsteroidal anti-inflammatory drugs on beta-catenin protein levels and catenin-related transcription in human colorectal cancer cells.	2004 Jul 5	15188006
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
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
Activation of protein kinase G Increases the expression of p21CIP1, p27KIP1, and histidine triad protein 1 through Sp1.	2008 Jul 1	18593937
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 `Sun Dec 18 21:18:07 UTC 2022` Edited by `admin` on `Sun Dec 18 21:18:07 UTC 2022`
Record UNII	K619IIG2R9
Record Status	`Validated (UNII)`
Record Version

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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

exisulind [INN]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/14/1387