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Tolrestat structure.svg
Tolrestat 3D ball.png
Clinical data
ATC code
Legal status
Legal status
  • Withdrawn from market
  • N-{[6-methoxy-5-(trifluoromethyl)-1-naphthyl]carbothioyl}-N-methylglycine
CAS Number
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
Formula C16H14F3NO3S
Molar mass 357.35 g·mol−1
3D model (JSmol)
  • CN(CC(=O)O)C(=S)C1=CC=CC2=C1C=CC(=C2C(F)(F)F)OC
  • 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) X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tolrestat (INN) (AY-27773) is an aldose reductase inhibitor [1] which was approved for the control of certain diabetic complications. [2]

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.

Related Research Articles

Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes.

The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.

<span class="mw-page-title-main">Aldose reductase</span> Enzyme

In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.

<span class="mw-page-title-main">Ranirestat</span> Chemical compound

Ranirestat is an aldose reductase inhibitor being developed for the treatment of diabetic neuropathy by Dainippon Sumitomo Pharma and PharmaKyorin. It has been granted orphan drug status. The drug is to be used orally.

<span class="mw-page-title-main">Epalrestat</span> Chemical compound

Epalrestat is a carboxylic acid derivative and a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy, which is one of the most common long-term complications in patients with diabetes mellitus. It reduces the accumulation of intracellular sorbitol which is believed to be the cause of diabetic neuropathy, retinopathy and nephropathy It is well tolerated, with the most commonly reported adverse effects being gastrointestinal issues such as nausea and vomiting, as well as increases in certain liver enzymes. Chemically, epalrestat is unusual in that it is a drug that contains a rhodanine group. Aldose reductase is the key enzyme in the polyol pathway whose enhanced activity is the basis of diabetic neuropathy. Aldose reductase inhibitors (ARI) target this enzyme. Out of the many ARIs developed, ranirestat and fidarestat are in the trial stage. Others have been discarded due to unacceptable adverse effects or weak efficacy. Epalrestat is the only ARI commercially available. It is easily absorbed into the neural tissue and inhibits the enzyme with minimum side effects.

<span class="mw-page-title-main">Monoamine oxidase B</span> Protein-coding gene in the species Homo sapiens

Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the MAOB gene.

<span class="mw-page-title-main">AKR1B1</span>

Aldo-keto reductase family 1, member B1 (AKR1B1), also known as aldose reductase, is an enzyme that is encoded by the AKR1B1 gene in humans. It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. The involvement of AKR1B1 in oxidative stress diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.

<span class="mw-page-title-main">Pravadoline</span> Chemical compound

Pravadoline (WIN 48,098) is an antinflammatory and analgesic drug with an IC50 of 4.9 μM and a Ki of 2511 nM at CB1, related in structure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as indometacin. It was developed in the 1980s as a new antiinflammatory and prostaglandin synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase (COX).

<span class="mw-page-title-main">Aldo-keto reductase family 1, member A1</span> Mammalian protein found in Homo sapiens

Alcohol dehydrogenase [NADP+] also known as aldehyde reductase or aldo-keto reductase family 1 member A1 is an enzyme that in humans is encoded by the AKR1A1 gene. AKR1A1 belongs to the aldo-keto reductase (AKR) superfamily. It catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols and catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol. Mutations in the AKR1A1 gene has been found associated with non-Hodgkin's lymphoma.

<span class="mw-page-title-main">AKR1B10</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1 member B10 is an enzyme that in humans is encoded by the AKR1B10 gene.

A galactosemic cataract is cataract which is associated with the consequences of galactosemia.

Bruce D. Roth is an American organic and medicinal chemist who trained at Iowa State University and the University of Rochester, and, at the age of 32, discovered atorvastatin, the statin-class drug sold as Lipitor that would become the largest-selling drug in pharmaceutical history. His honours include being named a 2008 Hero of Chemistry by the American Chemical Society, and being chosen as the Perkin Medal awardee, the highest honour given in the U.S. chemical industry, by the Society of Chemical Industry, American section in 2013.

<span class="mw-page-title-main">Depside</span>

A depside is a type of polyphenolic compound composed of two or more monocyclic aromatic units linked by an ester bond. Depsides are most often found in lichens, but have also been isolated from higher plants, including species of the Ericaceae, Lamiaceae, Papaveraceae and Myrtaceae.

<span class="mw-page-title-main">Aldo-keto reductase</span>

The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xylose reductase, rho crystallin, and many others.

<span class="mw-page-title-main">Sorbinil</span> Chemical compound

Sorbinil (INN) is an aldose reductase inhibitor being investigated for treatment of diabetic complications including neuropathy and retinopathy. Aldose reductase is an enzyme present in lens and brain that removes excess glucose by converting it to sorbitol. Sorbitol accumulation can lead to the development of cataracts in the lens and neuropathy in peripheral nerves. Sorbinil has been shown to inhibit aldose reductase in human brain and placenta and calf and rat lens. Sorbinil reduced sorbitol accumulation in rat lens and sciatic nerve of diabetic rats orally administered 0.25 mg/kg sorbinil.

<span class="mw-page-title-main">Alrestatin</span> Chemical compound

Alrestatin is an inhibitor of aldose reductase, an enzyme involved in the pathogenesis of complications of diabetes mellitus, including diabetic neuropathy.

<span class="mw-page-title-main">Sclerotiorin</span> Chemical compound

Sclerotiorin is an antimicrobial Penicillium frequentans isolate. Sclerotiorin is an aldose reductase inhibitor (IC50=0.4 μM) as well as a reversible lipoxygenase inhibitor (IC50=4.2 μM).

<span class="mw-page-title-main">Fidarestat</span> Chemical compound

Fidarestat (SNK-860) is an aldose reductase inhibitor under investigation for treatment of diabetic neuropathy.

<span class="mw-page-title-main">Targeted covalent inhibitors</span>

Targeted covalent inhibitors (TCIs) or Targeted covalent drugs are rationally designed inhibitors that bind and then bond to their target proteins. These inhibitors possess a bond-forming functional group of low chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a proximate nucleophilic residue at the target site to form a bond.

RAPTA is a class of experimental cancer drugs. They consist of a central ruthenium(II) atom complexed to an arene group, chlorides, and 1,3,5-triaza-7-phosphaadamantane (PTA) forming an organoruthenium half-sandwich compound. Other related ruthenium anti-cancer drugs include NAMI-A, KP1019 and BOLD-100.


  1. Sestanj K, Bellini F, Fung S, et al. (March 1984). "N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor". J. Med. Chem. 27 (3): 255–6. doi:10.1021/jm00369a003. PMID   6422042.
  2. Kador PF, Kinoshita JH, Sharpless NE (July 1985). "Aldose reductase inhibitors: a potential new class of agents for the pharmacological control of certain diabetic complications". J. Med. Chem. 28 (7): 841–9. doi:10.1021/jm00145a001. PMID   3925146.