Tolrestat
Explore a selection of our essential drug information below, or:
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- Withdrawn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
- Weight
- Average: 357.347
Monoisotopic: 357.064648624 - Chemical Formula
- C16H14F3NO3S
- Synonyms
- Tolrestat
- External IDs
- AY-27,773
- AY-27773
Pharmacology
- Indication
For the pharmacological control of certain diabetic complications.
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- Pharmacodynamics
Not Available
- Mechanism of action
Target Actions Organism ASigma non-opioid intracellular receptor 1 binderHumans AAldo-keto reductase family 1 member B1 inhibitorHumans UAldo-keto reductase family 1 member A1 Not Available Humans UAldo-keto reductase family 1 member B10 Not Available 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
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- 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
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- 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
- 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]
- 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]
- External Links
- PDB Entries
- 1ae4 / 1ah3 / 1zua / 2fzb / 2fzd / 2pdl / 6kik
- MSDS
- Download (567 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data
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
Property Value Source Water Solubility 0.0076 mg/mL ALOGPS logP 3.25 ALOGPS logP 3.35 Chemaxon logS -4.7 ALOGPS pKa (Strongest Acidic) 3.95 Chemaxon pKa (Strongest Basic) -4.9 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 49.77 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 87.89 m3·mol-1 Chemaxon Polarizability 32.11 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - 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 inhibitor Non-inhibitor 0.5796 CYP450 2D6 inhibitor Non-inhibitor 0.8088 CYP450 2C19 inhibitor Inhibitor 0.6071 CYP450 3A4 inhibitor 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0aor-0089000000-7bc08f0a04954b93a638 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0bt9-1019000000-299b10b7466445fc1b60 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00xr-9040000000-6de3aa012b2cff62927a Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0400-1094000000-9279039af75b02dc4c2b Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0gdi-0190000000-0323a2d24f30aedd6c33 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-014j-4090000000-f8c1f5640926acc31e77 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 180.23367 predictedDeepCCS 1.0 (2019) [M+H]+ 182.59166 predictedDeepCCS 1.0 (2019) [M+Na]+ 190.58812 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Binder
- General Function
- Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration (PubMed:16472803, PubMed:9341151). Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria. Plays a role in protecting cells against oxidative stress-induced cell death via its interaction with RNF112 (By similarity)
- Specific Function
- G protein-coupled opioid receptor activity
- Gene Name
- SIGMAR1
- Uniprot ID
- Q99720
- Uniprot Name
- Sigma non-opioid intracellular receptor 1
- Molecular Weight
- 25127.52 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols. Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosacharides, bile acids and xenobiotics substrates. Key enzyme in the polyol pathway, catalyzes reduction of glucose to sorbitol during hyperglycemia (PubMed:1936586). Reduces steroids and their derivatives and prostaglandins. Displays low enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal (PubMed:12732097, PubMed:19010934, PubMed:8343525). Catalyzes the reduction of diverse phospholipid aldehydes such as 1-palmitoyl-2-(5-oxovaleroyl)-sn -glycero-3-phosphoethanolamin (POVPC) and related phospholipid aldehydes that are generated from the oxydation of phosphotidylcholine and phosphatdyleethanolamides (PubMed:17381426). Plays a role in detoxifying dietary and lipid-derived unsaturated carbonyls, such as crotonaldehyde, 4-hydroxynonenal, trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GS-carbonyls) (PubMed:21329684)
- Specific Function
- aldose reductase (NADPH) activity
- Gene Name
- AKR1B1
- Uniprot ID
- P15121
- Uniprot Name
- Aldo-keto reductase family 1 member B1
- Molecular Weight
- 35853.125 Da
References
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- 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]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols (PubMed:10510318, PubMed:30538128). Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosaccharides and bile acids, with a preference for negatively charged substrates, such as glucuronate and succinic semialdehyde (PubMed:10510318, PubMed:30538128). Functions as a detoxifiying enzyme by reducing a range of toxic aldehydes (By similarity). Reduces methylglyoxal and 3-deoxyglucosone, which are present at elevated levels under hyperglycemic conditions and are cytotoxic (By similarity). Involved also in the detoxification of lipid-derived aldehydes like acrolein (By similarity). Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs, including the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN) (PubMed:11306097, PubMed:18276838). Also acts as an inhibitor of protein S-nitrosylation by mediating degradation of S-nitroso-coenzyme A (S-nitroso-CoA), a cofactor required to S-nitrosylate proteins (PubMed:30538128). S-nitroso-CoA reductase activity is involved in reprogramming intermediary metabolism in renal proximal tubules, notably by inhibiting protein S-nitrosylation of isoform 2 of PKM (PKM2) (By similarity). Also acts as a S-nitroso-glutathione reductase by catalyzing the NADPH-dependent reduction of S-nitrosoglutathione (PubMed:31649033). Displays no reductase activity towards retinoids (By similarity)
- Specific Function
- aldo-keto reductase (NADPH) activity
- Gene Name
- AKR1A1
- Uniprot ID
- P14550
- Uniprot Name
- Aldo-keto reductase family 1 member A1
- Molecular Weight
- 36572.71 Da
References
- 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]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols (PubMed:12732097, PubMed:18087047, PubMed:19013440, PubMed:19563777, PubMed:9565553). Displays strong enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal (PubMed:12732097, PubMed:18087047). Plays a critical role in detoxifying dietary and lipid-derived unsaturated carbonyls, such as crotonaldehyde, 4-hydroxynonenal, trans-2-hexenal, trans-2,4-hexadienal and their glutathione-conjugates carbonyls (GS-carbonyls) (PubMed:19013440, PubMed:19563777). Displays no reductase activity towards glucose (PubMed:12732097)
- Specific Function
- alcohol dehydrogenase (NADP+) activity
- Gene Name
- AKR1B10
- Uniprot ID
- O60218
- Uniprot Name
- Aldo-keto reductase family 1 member B10
- Molecular Weight
- 36019.295 Da
References
- 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 August 26, 2024 19:22