NAV

Tolrestat

Identification

Generic Name
Tolrestat
DrugBank Accession Number
DB02383
Background

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 sold under the tradename Alredase but was discontinued by Wyeth in 1997 because of the risk of severe liver toxicity and death.

Type
Small Molecule
Groups
Withdrawn
Structure
3D
Similar Structures
Weight
Average: 357.347
Monoisotopic: 357.064648624
Chemical Formula
C16H14F3NO3S
Synonyms
  • Tolrestat
External IDs
  • AY-27,773
  • AY-27773
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Pharmacology

Indication

For the pharmacological control of certain diabetic complications.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action
TargetActionsOrganism
UAlcohol dehydrogenase [NADP(+)]Not AvailableHumans
UAldo-keto reductase family 1 member B10Not AvailableHumans
UAldose reductase
inhibitor
Humans
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

Adverse Effects
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Toxicity

Oral, mouse: LD50 = 300 mg/kg; Oral, rabbit: LD50 = 3200 mg/kg; Oral, rat: LD50 = 980 mg/kg.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Products

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International/Other Brands
Alredase (Wyeth)

Categories

ATC Codes
A10XA01 — Tolrestat
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Naphthalenes
Sub Class
Not Available
Direct Parent
Naphthalenes
Alternative Parents
Alpha amino acids and derivatives / Anisoles / Alkyl aryl ethers / Thioamides / Thiocarboxylic acid amides / Monocarboxylic acids and derivatives / Carboxylic acids / Thiocarbonyl compounds / Organopnictogen compounds / Organonitrogen compounds
show 5 more
Substituents
Alkyl aryl ether / Alkyl fluoride / Alkyl halide / Alpha-amino acid or derivatives / Anisole / Aromatic homopolycyclic compound / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Ether
show 15 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
naphthalenes (CHEBI:48549)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
0T93LG5NMK
CAS number
82964-04-3
InChI Key
LUBHDINQXIHVLS-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

References

General References
  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. [Article]
  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. [Article]
KEGG Drug
D02323
KEGG Compound
C01621
PubChem Compound
53359
PubChem Substance
46508274
ChemSpider
48194
BindingDB
16314
RxNav
38386
ChEBI
48549
ChEMBL
CHEMBL436
ZINC
ZINC000003780343
Therapeutic Targets Database
DNC001455
PDBe Ligand
TOL
Wikipedia
Tolrestat
PDB Entries
1ae4 / 1ah3 / 1zua / 2fzb / 2fzd / 2pdl / 6kik
MSDS
Download (567 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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 Solubility0.0076 mg/mLALOGPS
logP3.25ALOGPS
logP3.35Chemaxon
logS-4.7ALOGPS
pKa (Strongest Acidic)3.95Chemaxon
pKa (Strongest Basic)-4.9Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area49.77 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity87.89 m3·mol-1Chemaxon
Polarizability32.11 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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 inhibitorNon-inhibitor0.5796
CYP450 2D6 inhibitorNon-inhibitor0.8088
CYP450 2C19 inhibitorInhibitor0.6071
CYP450 3A4 inhibitorNon-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
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/MSsplash10-0aor-0089000000-7bc08f0a04954b93a638
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0bt9-1019000000-299b10b7466445fc1b60
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00xr-9040000000-6de3aa012b2cff62927a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0400-1094000000-9279039af75b02dc4c2b
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gdi-0190000000-0323a2d24f30aedd6c33
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-014j-4090000000-f8c1f5640926acc31e77
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-180.23367
predicted
DeepCCS 1.0 (2019)
[M+H]+182.59166
predicted
DeepCCS 1.0 (2019)
[M+Na]+190.58812
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Alcohol dehydrogenase [NADP(+)]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
L-glucuronate reductase activity
Specific Function
Catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols. Catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyd...
Gene Name
AKR1A1
Uniprot ID
P14550
Uniprot Name
Alcohol dehydrogenase [NADP(+)]
Molecular Weight
36572.71 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. [Article]
Details2. Aldo-keto reductase family 1 member B10
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Retinal dehydrogenase activity
Specific Function
Acts as all-trans-retinaldehyde reductase. Can efficiently reduce aliphatic and aromatic aldehydes, and is less active on hexoses (in vitro). May be responsible for detoxification of reactive aldeh...
Gene Name
AKR1B10
Uniprot ID
O60218
Uniprot Name
Aldo-keto reductase family 1 member B10
Molecular Weight
36019.295 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. [Article]
Details3. Aldose reductase
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Glyceraldehyde oxidoreductase activity
Specific Function
Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
Gene Name
AKR1B1
Uniprot ID
P15121
Uniprot Name
Aldose reductase
Molecular Weight
35853.125 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  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. [Article]

Drug created at June 13, 2005 13:24 / Updated at February 21, 2021 18:51