TOLRESTAT

Details

Stereochemistry	ACHIRAL
Molecular Formula	C16H14F3NO3S
Molecular Weight	357.347
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC=C2C(=CC=CC2=C1C(F)(F)F)C(=S)N(C)CC(O)=O

InChI

InChIKey=LUBHDINQXIHVLS-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C16H14F3NO3S
Molecular Weight	357.347
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.corriere.it/salute/dizionario/tolrestat/index.shtml
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800002966 https://en.wikipedia.org/wiki/Tolrestat https://www.ncbi.nlm.nih.gov/pubmed/8343611

Tolrestat is an orally active aldose reductase inhibitor. It was used for the pharmacological control of certain diabetic complications. It was discontinued by Wyeth in 1997 because of the risk of severe liver toxicity and death.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Aldose reductase 45 Target ID: CHEMBL2622 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3925146	Inhibitor 8504		35.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Diabetic neuropathy 23 Sources: http://www.ndrugs.com/?s=alredase https://www.ncbi.nlm.nih.gov/pubmed/7497865	Primary		Approved 8583	Alredase Approved Use Treatment of patients suffering from clinically symptomatic diabetic neuropathy Launch Date 1992

C_max

Value	Dose	Analyte	Population
11.3 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
11.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
14.8 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
27 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
21 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
30 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
23 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
15.9 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
18.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
18.2 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
18.5 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED
19 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

AUC

Value	Dose	Analyte	Population
55.1 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
57.1 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
86 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
104 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED
193 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

T_1/2

Value	Dose	Analyte	Population
13 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
13.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
13.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
11.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
17.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
15.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
15.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
10.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
10.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
10.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
11.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED
16.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1544287/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

F_unbound

Value	Dose	Analyte	Population
0.64% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
0.64% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8529328/	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLRESTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED
0.76% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
0.73% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
0.77% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
0.8% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8681485/	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	TOLRESTAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

PubMed

Title	Date	PubMed
X-ray structure of the V301L aldo-keto reductase 1B10 complexed with NADP(+) and the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity.	2013-02-25	23295227
Low peripheral nerve conduction velocities and amplitudes are strongly related to diabetic microvascular complications in type 1 diabetes: the EURODIAB Prospective Complications Study.	2010-12	20823346
Diabetic neuropathy: a cross-sectional study of the relationships among tests of neurophysiology.	2010-12	20805259
Prevention of diabetic eye disease: the commonest cause of blindness in individuals younger than 65 years.	2010-11-15	21139669
Aldose reductase inhibitor ameliorates renal vascular endothelial growth factor expression in streptozotocin-induced diabetic rats.	2010-05	20376891
Synthesis and biological evaluation of [1,2,4]triazino[4,3-a] benzimidazole acetic acid derivatives as selective aldose reductase inhibitors.	2010-03	19962793
Rat aldose reductase-like protein (AKR1B14) efficiently reduces the lipid peroxidation product 4-oxo-2-nonenal.	2010	21048316
Selective inhibition of the tumor marker AKR1B10 by antiinflammatory N-phenylanthranilic acids and glycyrrhetic acid.	2010	20460771
Reductive metabolism of AGE precursors: a metabolic route for preventing AGE accumulation in cardiovascular tissue.	2009-11	19651811
Aldose reductase protects against early atherosclerotic lesion formation in apolipoprotein E-null mice.	2009-10-09	19729598
Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase.	2009-09	19616461
Kinetic studies of AKR1B10, human aldose reductase-like protein: endogenous substrates and inhibition by steroids.	2009-07-01	19464995
Elevated triglycerides correlate with progression of diabetic neuropathy.	2009-07	19411614
Advances in pharmacological strategies for the prevention of cataract development.	2009-04-23	19384010
Characterization of a rat NADPH-dependent aldo-keto reductase (AKR1B13) induced by oxidative stress.	2009-03-16	18845131
The cycle of genome-directed medicine.	2009-02-02	19341487
Correlation of binding constants and molecular modelling of inhibitors in the active sites of aldose reductase and aldehyde reductase.	2009-02-01	19121944
Prostaglandin F2alpha synthase activities of aldo-keto reductase 1B1, 1B3 and 1B7.	2009-02	19010934
Stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long-term treatment with an aldose reductase inhibitor, epalrestat.	2008-07	18644069
Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.	2008-06-20	18495158
Diabetic retinopathy: an update.	2008-04-18	18417817
Role of nitric oxide in regulating aldose reductase activation in the ischemic heart.	2008-04-04	18223294
C-Peptide effects on renal physiology and diabetes.	2008	18509500
Effect of C-peptide on diabetic neuropathy in patients with type 1 diabetes.	2008	18350117
Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10.	2007-12-26	18087047
Tracing changes in protonation: a prerequisite to factorize thermodynamic data of inhibitor binding to aldose reductase.	2007-11-09	17905306
Aldose reductase inhibitors for the treatment of diabetic polyneuropathy.	2007-10-17	17943821
Aldose reductase-regulated tumor necrosis factor-alpha production is essential for high glucose-induced vascular smooth muscle cell growth.	2007-09	17584970
Evidence for a novel binding site conformer of aldose reductase in ligand-bound state.	2007-05-25	17418233
PocketPicker: analysis of ligand binding-sites with shape descriptors.	2007-03-13	17880740
Current concepts in targeted therapies for the pathophysiology of diabetic microvascular complications.	2007	18200803
Inhibition of aldose reductase prevents lipopolysaccharide-induced inflammatory response in human lens epithelial cells.	2006-12	17122129
Mediation of aldose reductase in lipopolysaccharide-induced inflammatory signals in mouse peritoneal macrophages.	2006-11	17174561
Expect the unexpected or caveat for drug designers: multiple structure determinations using aldose reductase crystals treated under varying soaking and co-crystallisation conditions.	2006-10-13	16952371
Phenolic marine natural products as aldose reductase inhibitors.	2006-10	17067167
Contribution of aldose reductase to diabetic hyperproliferation of vascular smooth muscle cells.	2006-04	16567509
Assessment of basic indirect pharmacodynamic response models with physiological limits.	2006-04	16547797
High-resolution crystal structure of aldose reductase complexed with the novel sulfonyl-pyridazinone inhibitor exhibiting an alternative active site anchoring group.	2006-02-10	16337231
Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options.	2005-05	15814847
Requirement of aldose reductase for the hyperglycemic activation of protein kinase C and formation of diacylglycerol in vascular smooth muscle cells.	2005-03	15734861
Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one as potent in vitro and in vivo aldose reductase inhibitors.	2005-01-17	15598571
Aldose reductase-catalyzed reduction of aldehyde phospholipids.	2004-12-17	15465833
Activation of nuclear factor-kappaB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase.	2004-11	15504972
Inhibition of aldose reductase attenuates TNF-alpha-induced expression of adhesion molecules in endothelial cells.	2004-08	15284221
Aldose reductase regulates TNF-alpha-induced cell signaling and apoptosis in vascular endothelial cells.	2004-07-16	15251463
Rational design of an indolebutanoic acid derivative as a novel aldose reductase inhibitor based on docking and 3D QSAR studies of phenethylamine derivatives.	2003-12-18	14667216
Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: consequences for retinoid metabolism.	2003-08-01	12732097
Novel, highly potent aldose reductase inhibitors: cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives.	2003-04-10	12672241
Aldose reductase inhibitors: a potential new class of agents for the pharmacological control of certain diabetic complications.	1985-07	3925146
N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor.	1984-03	6422042

Patents

Sample Use Guides

In Vivo Use Guide

200 mg 1 time a day, in the morning before breakfast

Route of Administration: Oral

In Vitro Use Guide

In the lens, a 18% inhibition (p < 0.01) was observed in the presence of 8 micromol/L Tolrestat. In the optic nerve, a 12% (p < 0.05) and a 21% (p < 0.01) reduction was recorded at 4 and 8 micromol/L Tolrestat, respectively.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 19:26:12 GMT 2025` Edited by `admin` on `Mon Mar 31 19:26:12 GMT 2025`
Record UNII	0T93LG5NMK
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TOLRESTAT

Official Name

English

ALREDASE

Preferred Name

English

Tolrestat [WHO-DD]

Common Name

English

tolrestat [INN]

Common Name

English

TOLRESTAT [MART.]

Common Name

English

TOLRESTAT [MI]

Common Name

English

AY-27,773

Code

English

TOLRESTAT [USAN]

Common Name

English

N-[6-Methoxythio-5-(trifluoromethyl)-1-naphthoyl]sarcosine

Systematic Name

English

AY-27773

Code

English

GLYCINE, N-((6-METHOXY-5-(TRIFLUOROMETHYL)-1-NAPHTHALENYL)THIOXOMETHYL)-N-METHYL-

Systematic Name

English

Classification Tree Code System Code

WHO-VATC

QA10XA01