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
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-
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15230629
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
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1827 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11358813 |
112.0 µM [IC50] | ||
Target ID: CHEMBL2093863 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11358813 |
116.0 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
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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 | Co-administered | 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 |
T1/2
Value | Dose | Co-administered | 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 |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical 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] | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/ |
yes | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/ |
yes | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/ |
yes | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/ |
yes | |||
yes | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/ |
yes | |||
yes | ||||
yes | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/17985343/ |
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
like | ||||
likely | ||||
likely | ||||
likely | ||||
likely | ||||
likely | ||||
no | ||||
no | ||||
no | ||||
yes [Km 15 uM] | ||||
yes [Km 34.1 uM] | ||||
yes [Km 44.6 uM] | ||||
yes [Km 5.2 uM] |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process. | 1999 Jul 15 |
|
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 |
|
Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation. | 2000 Feb |
|
Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. | 2000 Jul 1 |
|
Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. | 2000 Oct |
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Sulindac-associated choledocholithiasis. | 2001 Jul |
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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 |
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Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK1. | 2001 May 11 |
|
Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells. | 2001 Nov |
|
Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy. | 2001 Sep |
|
Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. | 2003 Nov 28 |
|
Exisulind and related compounds inhibit expression and function of the androgen receptor in human prostate cancer cells. | 2003 Oct 15 |
|
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 |
|
Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells. | 2006 May |
|
Gene expression profiling in R-flurbiprofen-treated prostate cancer: R-Flurbiprofen regulates prostate stem cell antigen through activation of AKT kinase. | 2006 Nov 15 |
|
Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon. | 2007 Apr 1 |
|
Exisulind in combination with celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence. | 2007 Oct 1 |
|
Malignant transformation of normal enterocytes following downregulation of Bak expression. | 2008 |
|
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 |
|
Activation of protein kinase G Increases the expression of p21CIP1, p27KIP1, and histidine triad protein 1 through Sp1. | 2008 Jul 1 |
|
Sulindac and its metabolites induce carcinogen metabolizing enzymes in human colon cancer cells. | 2008 Mar 1 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16891869
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21515355
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.
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Classification Tree | Code System | Code | ||
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EU-Orphan Drug |
EU/3/14/1387
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NCI_THESAURUS |
C1323
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FDA ORPHAN DRUG |
79293
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3219
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CHEMBL488025
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64212
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m5226
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59864-04-9
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5472495
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EXISULIND
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K619IIG2R9
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C025463
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100000177152
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ACTIVE MOIETY
PARENT (METABOLITE)