Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C23H27N3O6S |
Molecular Weight | 473.542 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 3 / 3 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
N[C@@H](CCC(=O)N[C@@H](CSCC1=CC=CC=C1)C(=O)N[C@@H](C(O)=O)C2=CC=CC=C2)C(O)=O
InChI
InChIKey=ZPSKWMFLCHMEOY-CMKODMSKSA-N
InChI=1S/C23H27N3O6S/c24-17(22(29)30)11-12-19(27)25-18(14-33-13-15-7-3-1-4-8-15)21(28)26-20(23(31)32)16-9-5-2-6-10-16/h1-10,17-18,20H,11-14,24H2,(H,25,27)(H,26,28)(H,29,30)(H,31,32)/t17-,18-,20+/m0/s1
Molecular Formula | C23H27N3O6S |
Molecular Weight | 473.542 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 3 / 3 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Ezatiostat (TLK199) [γ-glutamyl-S-(benzyl)cysteinyl-R-phenyl glycine diethyl ester] is an inhibitor of Glutathione S-transferase P1–1 (GSTπ). The drug is a peptidomimetic of GSH (glutathione), esterified to enhance cellular uptake and designed to bind to the “G-site” of GSTP1–1. Independent of catalysis inhibition, TLK199 also disrupts the protein:protein interaction site(s) between GSTP1–1 and JNK1. Telik Inc was developing TLK-199 for the potential prevention of myelosuppression in blood diseases, namely myelodysplastic syndrome.
Originator
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8289195
Curator's Comment: reference retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11408560
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL3902 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11408560 |
400.0 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
Doses
Dose | Population | Adverse events |
---|---|---|
3000 mg 2 times / day multiple, oral Highest studied dose Dose: 3000 mg, 2 times / day Route: oral Route: multiple Dose: 3000 mg, 2 times / day Sources: Page: p.6537 |
unhealthy n = 12 Health Status: unhealthy Condition: myelodysplastic syndrome Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.6537 |
Disc. AE: Nausea... AEs leading to discontinuation/dose reduction: Nausea (8.3%) Sources: Page: p.6537 |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Nausea | 8.3% Disc. AE |
3000 mg 2 times / day multiple, oral Highest studied dose Dose: 3000 mg, 2 times / day Route: oral Route: multiple Dose: 3000 mg, 2 times / day Sources: Page: p.6537 |
unhealthy n = 12 Health Status: unhealthy Condition: myelodysplastic syndrome Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.6537 |
PubMed
Title | Date | PubMed |
---|---|---|
Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. | 2001 Jul |
|
Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid. | 2004 Aug |
|
TLK-199 (Telik). | 2005 Aug |
Patents
Sample Use Guides
Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles.
Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.
Route of Administration:
Other
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11408560
Wild type HL60 cells were induced to undergo apoptosis by 8- and 24-h treatments with 10 and 50 uM ezatiostat (TLK199). Additive apoptotic effects were seen when HL60 cells were co-treated with 50 uM TLK199 and UV.
Substance Class |
Chemical
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Record UNII |
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