Ezatiostat

Identification

Name
Ezatiostat
Accession Number
DB05460  (DB12215)
Type
Small Molecule
Groups
Investigational
Description

Ezatiostat is investigated in clinical trials for treating myelodysplastic syndrome. This compound belongs to the peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another. This medication is known to target Glutathione S-transferase P. Ezatiostat is a small molecule drug that is an analog inhibitor of glutathione S-transferase P1-1. It acts intracellularly on the MAPK signaling pathway by activating ERK2. Ezatiostat has myelostimulant activity in preclinical rodent models and human bone marrow cultures, and differentiates granulocytes and monocytes in HL60 cells. Ezatiostat is a candidate designed to stimulate the formation of bone marrow cells that are precursors to granulocytes and monocytes (white blood cells), erythrocytes (red blood cells) and platelets. Many conditions are characterized by depleted bone marrow, including myelodysplastic syndrome (MDS), a form of pre-leukemia in which the bone marrow produces insufficient levels of one or more of the 3 major blood elements (white blood cells, red blood cells and platelets). It might also be relevant as an adjunct therapy since a reduction in blood cell levels is also a common, toxic effect of many standard chemotherapeutic drugs.

Structure
Thumb
Synonyms
  • gamma-Glutamyl-S-(benzyl)-cysteinyl-R(-)-phenylglycine diethyl ester
External IDs
TER 199 / Ter-199 / Terrapin 199 / TLK-199 / TLK199
International/Other Brands
Telintra
Categories
UNII
057D10I8S8
CAS number
168682-53-9
Weight
Average: 529.648
Monoisotopic: 529.224656557
Chemical Formula
C27H35N3O6S
InChI Key
GWEJFLVSOGNLSS-WPFOTENUSA-N
InChI
InChI=1S/C27H35N3O6S/c1-3-35-26(33)21(28)15-16-23(31)29-22(18-37-17-19-11-7-5-8-12-19)25(32)30-24(27(34)36-4-2)20-13-9-6-10-14-20/h5-14,21-22,24H,3-4,15-18,28H2,1-2H3,(H,29,31)(H,30,32)/t21-,22-,24+/m0/s1
IUPAC Name
ethyl (2S)-2-amino-4-{[(1R)-2-(benzylsulfanyl)-1-{[(1R)-2-ethoxy-2-oxo-1-phenylethyl]carbamoyl}ethyl]carbamoyl}butanoate
SMILES
CCOC(=O)[[email protected]@H](N)CCC(=O)N[[email protected]@H](CSCC1=CC=CC=C1)C(=O)N[[email protected]@H](C(=O)OCC)C1=CC=CC=C1

Pharmacology

Indication

Investigated for use/treatment in myelodysplastic syndrome.

Structured Indications
Not Available
Pharmacodynamics
Not Available
Mechanism of action
TargetActionsOrganism
UGlutathione S-transferase PNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Hamilton D, Batist G: TLK-199 (Telik). IDrugs. 2005 Aug;8(8):662-9. [PubMed:16044376]
External Links
PubChem Compound
5310939
PubChem Substance
175427010
ChemSpider
4470493
ChEMBL
CHEMBL2110585

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentMyelodysplastic Syndromes (MDS)1
2CompletedTreatmentMyelodysplastic Syndromes (MDS)1
2TerminatedSupportive CareLung Cancer Non-Small Cell Cancer (NSCLC)1
2TerminatedTreatmentMyelodysplastic Syndromes (MDS)2
2TerminatedTreatmentNeutropenia, Severe Chronic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00245 mg/mLALOGPS
logP2.39ALOGPS
logP2.42ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)11.8ChemAxon
pKa (Strongest Basic)7.18ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area136.82 Å2ChemAxon
Rotatable Bond Count17ChemAxon
Refractivity141.82 m3·mol-1ChemAxon
Polarizability57.5 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.932
Blood Brain Barrier+0.5139
Caco-2 permeable-0.7903
P-glycoprotein substrateSubstrate0.7299
P-glycoprotein inhibitor IInhibitor0.5322
P-glycoprotein inhibitor IINon-inhibitor0.9937
Renal organic cation transporterNon-inhibitor0.8903
CYP450 2C9 substrateNon-substrate0.8782
CYP450 2D6 substrateNon-substrate0.8538
CYP450 3A4 substrateNon-substrate0.5726
CYP450 1A2 substrateNon-inhibitor0.9101
CYP450 2C9 inhibitorNon-inhibitor0.8228
CYP450 2D6 inhibitorNon-inhibitor0.766
CYP450 2C19 inhibitorNon-inhibitor0.6553
CYP450 3A4 inhibitorInhibitor0.5834
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.704
Ames testNon AMES toxic0.778
CarcinogenicityNon-carcinogens0.8939
BiodegradationNot ready biodegradable0.9409
Rat acute toxicity2.2434 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9864
hERG inhibition (predictor II)Non-inhibitor0.7148
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Oligopeptides
Alternative Parents
Glutamine and derivatives / Alpha amino acid esters / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Cysteine and derivatives / Fatty acid esters / N-acyl amines / Dicarboxylic acids and derivatives / Benzene and substituted derivatives / Carboxylic acid esters
show 8 more
Substituents
Alpha-oligopeptide / Glutamine or derivatives / Alpha-amino acid ester / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Cysteine or derivatives / N-substituted-alpha-amino acid / Alpha-amino acid or derivatives / Fatty acid ester / Fatty amide
show 25 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
S-nitrosoglutathione binding
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name
GSTP1
Uniprot ID
P09211
Uniprot Name
Glutathione S-transferase P
Molecular Weight
23355.625 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235]

Drug created on November 18, 2007 11:25 / Updated on December 01, 2017 15:36