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Identification
NameTolrestat
Accession NumberDB02383  (EXPT03082)
TypeSmall Molecule
GroupsWithdrawn
Description

Tolrestat (INN) (AY-27773) is an aldose reductase inhibitor which was approved for the control of certain diabetic complications. While it was approved for marketed in several countries, it failed a Phase III trial in the U.S. due to toxicity and never received FDA approval. It was discontinued by Wyeth in 1997 because of the risk of severe liver toxicity and death. It was sold under the tradename Alredase. [Wikipedia]

Structure
Thumb
SynonymsNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
AlredaseWyeth
Brand mixturesNot Available
SaltsNot Available
CategoriesNot Available
CAS number82964-04-3
WeightAverage: 357.347
Monoisotopic: 357.064648624
Chemical FormulaC16H14F3NO3S
InChI KeyLUBHDINQXIHVLS-UHFFFAOYSA-N
InChI
InChI=1S/C16H14F3NO3S/c1-20(8-13(21)22)15(24)11-5-3-4-10-9(11)6-7-12(23-2)14(10)16(17,18)19/h3-7H,8H2,1-2H3,(H,21,22)
IUPAC Name
2-{1-[6-methoxy-5-(trifluoromethyl)naphthalen-1-yl]-N-methylmethanethioamido}acetic acid
SMILES
COC1=C(C2=CC=CC(C(=S)N(C)CC(O)=O)=C2C=C1)C(F)(F)F
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as naphthalenes. These are compounds containing a naphthalene moiety, which consists of two fused benzene rings.
KingdomOrganic compounds
Super ClassBenzenoids
ClassNaphthalenes
Sub ClassNot Available
Direct ParentNaphthalenes
Alternative Parents
Substituents
  • Naphthalene
  • Alpha-amino acid or derivatives
  • Anisole
  • Alkyl aryl ether
  • Thioamide
  • Tertiary amine
  • Monocarboxylic acid or derivatives
  • Ether
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Alkyl halide
  • Alkyl fluoride
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the pharmacological control of certain diabetic complications.
PharmacodynamicsNot Available
Mechanism of actionNot Available
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityOral, mouse: LD50 = 300 mg/kg; Oral, rabbit: LD50 = 3200 mg/kg; Oral, rat: LD50 = 980 mg/kg.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9968
Blood Brain Barrier+0.8123
Caco-2 permeable+0.5707
P-glycoprotein substrateNon-substrate0.5424
P-glycoprotein inhibitor IInhibitor0.5239
P-glycoprotein inhibitor IINon-inhibitor0.7162
Renal organic cation transporterNon-inhibitor0.8474
CYP450 2C9 substrateNon-substrate0.7365
CYP450 2D6 substrateNon-substrate0.7612
CYP450 3A4 substrateSubstrate0.5891
CYP450 1A2 substrateInhibitor0.6148
CYP450 2C9 substrateNon-inhibitor0.5796
CYP450 2D6 substrateNon-inhibitor0.8088
CYP450 2C19 substrateInhibitor0.6071
CYP450 3A4 substrateNon-inhibitor0.6444
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6797
Ames testNon AMES toxic0.663
CarcinogenicityNon-carcinogens0.7909
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.8458 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9767
hERG inhibition (predictor II)Non-inhibitor0.5071
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0076 mg/mLALOGPS
logP3.25ALOGPS
logP3.35ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)3.95ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area49.77 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity87.89 m3·mol-1ChemAxon
Polarizability32.08 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Sestanj K, Bellini F, Fung S, Abraham N, Treasurywala A, Humber L, Simard-Duquesne N, Dvornik D: N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor. J Med Chem. 1984 Mar;27(3):255-6. Pubmed
  2. Kador PF, Kinoshita JH, Sharpless NE: Aldose reductase inhibitors: a potential new class of agents for the pharmacological control of certain diabetic complications. J Med Chem. 1985 Jul;28(7):841-9. Pubmed
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSDownload (567 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Aldose reductase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Aldose reductase P15121 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. 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

2. Alcohol dehydrogenase [NADP(+)]

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Alcohol dehydrogenase [NADP(+)] P14550 Details

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

3. Aldo-keto reductase family 1 member B10

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Aldo-keto reductase family 1 member B10 O60218 Details

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:18