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 7701	Colorectal cancer Small intestine cancer Non-small cell lung cancer Prostate cancer	112 µM [IC50]
Phosphodiesterase 4 49 Target ID: CHEMBL2093863 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11358813	Inhibitor 7701		116 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase
Colorectal cancer 94 Sources: https://clinicaltrials.gov/ct2/show/NCT00026468	Primary	Phosphodiesterase 5A	Phase III 650
Small intestine cancer 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00026468	Primary	Phosphodiesterase 5A	Phase III 650
Non-small cell lung cancer 195 Sources: https://clinicaltrials.gov/ct2/show/NCT00085826	Primary	Phosphodiesterase 5A	Phase III 650
Prostate cancer 161 Sources: https://clinicaltrials.gov/ct2/show/NCT00078910	Primary	Phosphodiesterase 5A	Phase II

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
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
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
Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK1.	2001 May 11	11278263
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
Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation.	2002 Nov 1	12392815
Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer.	2003 Nov 28	14506281
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
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
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
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)`
Record Version

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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