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=C(C2=C(C=C1)C(=CC=C2)C(=S)N(C)CC(O)=O)C(F)(F)F

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

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 44 Target ID: CHEMBL2622 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3925146	Inhibitor 8297		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 8429	Alredase Approved Use Treatment of patients suffering from clinically symptomatic diabetic neuropathy Launch Date 1992

PubMed

Title	Date	PubMed
Molecular modeling of the aldose reductase-inhibitor complex based on the X-ray crystal structure and studies with single-site-directed mutants.	2000 Mar 23	10737739
Aldose reductase inhibitors.	2001 Dec	12164386
Involvement of aldose reductase in the metabolism of atherogenic aldehydes.	2001 Jan 30	11306075
Nitric oxide prevents aldose reductase activation and sorbitol accumulation during diabetes.	2002 Oct	12351453
Novel, highly potent aldose reductase inhibitors: cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives.	2003 Apr 10	12672241
Rational design of an indolebutanoic acid derivative as a novel aldose reductase inhibitor based on docking and 3D QSAR studies of phenethylamine derivatives.	2003 Dec 18	14667216
Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF-alpha in human lens epithelial cells.	2003 Feb	12490536
Role of aldose reductase in TNF-alpha-induced apoptosis of vascular endothelial cells.	2003 Feb 1	12604246
Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides.	2003 Jan 30	12540241
Inhibition of aldose reductase attenuates TNF-alpha-induced expression of adhesion molecules in endothelial cells.	2004 Aug	15284221
Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one as potent in vitro and in vivo aldose reductase inhibitors.	2005 Jan 17	15598571
Contribution of aldose reductase to diabetic hyperproliferation of vascular smooth muscle cells.	2006 Apr	16567509
Inhibition of aldose reductase prevents lipopolysaccharide-induced inflammatory response in human lens epithelial cells.	2006 Dec	17122129
Mediation of aldose reductase in lipopolysaccharide-induced inflammatory signals in mouse peritoneal macrophages.	2006 Nov	17174561
Phenolic marine natural products as aldose reductase inhibitors.	2006 Oct	17067167
Current concepts in targeted therapies for the pathophysiology of diabetic microvascular complications.	2007	18200803
Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10.	2007 Dec 26	18087047
PocketPicker: analysis of ligand binding-sites with shape descriptors.	2007 Mar 13	17880740
Evidence for a novel binding site conformer of aldose reductase in ligand-bound state.	2007 May 25	17418233
Tracing changes in protonation: a prerequisite to factorize thermodynamic data of inhibitor binding to aldose reductase.	2007 Nov 9	17905306
Aldose reductase inhibitors for the treatment of diabetic polyneuropathy.	2007 Oct 17	17943821
Aldose reductase-regulated tumor necrosis factor-alpha production is essential for high glucose-induced vascular smooth muscle cell growth.	2007 Sep	17584970
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
Role of nitric oxide in regulating aldose reductase activation in the ischemic heart.	2008 Apr 4	18223294
Stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long-term treatment with an aldose reductase inhibitor, epalrestat.	2008 Jul	18644069
Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features.	2008 Jun 20	18495158
Diabetic retinopathy: an update.	2008 May-Jun	18417817
Prostaglandin F2alpha synthase activities of aldo-keto reductase 1B1, 1B3 and 1B7.	2009 Feb	19010934
Correlation of binding constants and molecular modelling of inhibitors in the active sites of aldose reductase and aldehyde reductase.	2009 Feb 1	19121944
The cycle of genome-directed medicine.	2009 Feb 2	19341487
Elevated triglycerides correlate with progression of diabetic neuropathy.	2009 Jul	19411614
Kinetic studies of AKR1B10, human aldose reductase-like protein: endogenous substrates and inhibition by steroids.	2009 Jul 1	19464995
Characterization of a rat NADPH-dependent aldo-keto reductase (AKR1B13) induced by oxidative stress.	2009 Mar 16	18845131
Advances in pharmacological strategies for the prevention of cataract development.	2009 May-Jun	19384010
Reductive metabolism of AGE precursors: a metabolic route for preventing AGE accumulation in cardiovascular tissue.	2009 Nov	19651811
Aldose reductase protects against early atherosclerotic lesion formation in apolipoprotein E-null mice.	2009 Oct 9	19729598
Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase.	2009 Sep	19616461
Diabetic neuropathy: a cross-sectional study of the relationships among tests of neurophysiology.	2010 Dec	20805259

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.

Name

Type

Language

TOLRESTAT

Official 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

ALREDASE

Brand 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