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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
SaltsNot Available
Brand names
NameCompany
AlredaseWyeth
Brand mixturesNot 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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassAcenes and Derivatives
SubclassNaphthalenes
Direct parentNaphthalenes
Alternative parentsAlpha Amino Acids and Derivatives; Anisoles; Alkyl Aryl Ethers; Thioamides; Tertiary Amines; Enolates; Carboxylic Acids; Thiocarboxylic Acid Amides; Polyamines; Organofluorides; Alkyl Fluorides
Substituentsphenol ether; anisole; alkyl aryl ether; benzene; thioamide; tertiary amine; polyamine; thiocarboxylic acid amide; enolate; thiocarboxylic acid derivative; carboxylic acid derivative; carboxylic acid; ether; organohalogen; organofluoride; amine; alkyl halide; alkyl fluoride; organonitrogen compound
Classification descriptionThis compound belongs to the naphthalenes. These are compounds containing a naphthalene moiety, which consists of two fused benzene rings.
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
Property Value Probability
Human Intestinal Absorption + 0.9968
Blood Brain Barrier + 0.8123
Caco-2 permeable + 0.5707
P-glycoprotein substrate Non-substrate 0.5424
P-glycoprotein inhibitor I Inhibitor 0.5239
P-glycoprotein inhibitor II Non-inhibitor 0.7162
Renal organic cation transporter Non-inhibitor 0.8474
CYP450 2C9 substrate Non-substrate 0.7365
CYP450 2D6 substrate Non-substrate 0.7612
CYP450 3A4 substrate Substrate 0.5891
CYP450 1A2 substrate Inhibitor 0.6148
CYP450 2C9 substrate Non-inhibitor 0.5796
CYP450 2D6 substrate Non-inhibitor 0.8088
CYP450 2C19 substrate Inhibitor 0.6071
CYP450 3A4 substrate Non-inhibitor 0.6444
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6797
Ames test Non AMES toxic 0.663
Carcinogenicity Non-carcinogens 0.7909
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.8458 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9767
hERG inhibition (predictor II) Non-inhibitor 0.5071
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility7.60e-03 g/lALOGPS
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 area49.77ChemAxon
rotatable bond count5ChemAxon
refractivity87.89ChemAxon
polarizability32.08ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
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
ResourceLink
KEGG DrugD02323
KEGG CompoundC01621
PubChem Compound53359
PubChem Substance46508274
ChemSpider48194
BindingDB16314
ChEBI48549
ChEMBL
Therapeutic Targets DatabaseDNC001455
HETTOL
WikipediaTolrestat
ATC CodesA10XA01
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSshow(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