N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor

Sestanj, K.; Bellini, F.; Fung, Steven; Abraham, N. A.; Treasurywala, Adi M.; Humber, Leslie G.; Simard‐Duquesne, N.; Dvornik, D.

doi:10.1021/jm00369a003

Cited by 114 publications

(47 citation statements)

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“…Compounds PS01-PS12 were also assayed for their potency to inhibit SD [25] and two other enzymes not involved in the polyol pathway, namely, ALR1 [26] and GR [27]. Sorbinil [28] and tolrestat [29] were used as the reference standards. Compound PS11 was investigated in vivo for their effectiveness to prevent cataract development in severely galactosemic rats [28].…”

Section: Biochemistry and Pharmacologymentioning

confidence: 99%

RETRACTED: Synthesis and biological evaluation of [1,2,4]triazino[4,3-a] benzimidazole acetic acid derivatives as selective aldose reductase inhibitors

Sahoo

Behera²

2010

European Journal of Medicinal Chemistry

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Section: Biochemistry and Pharmacologymentioning

confidence: 99%

RETRACTED: Synthesis and biological evaluation of [1,2,4]triazino[4,3-a] benzimidazole acetic acid derivatives as selective aldose reductase inhibitors

Sahoo

Behera²

2010

European Journal of Medicinal Chemistry

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“…This fact agrees with the polyol model because galactose is a better substrate than glucose for AR in vitro, and its reduction product galactitol is not further converted to other metabolites, resulting in faster buildup of this polyol. Additional evidence for the polyol model came from the fact that several AR inhibitors could suppress cataract formation in experimentally induced diabetic animals (8)(9)(10). However, these drugs may inhibit AR by nonspecific hydrophobic interactions (11,12), and their beneficial effects may be derived from the inhibition of other enzymes.…”

mentioning

confidence: 99%

Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens.

Lee

Chung

1995

Proc. Natl. Acad. Sci. U.S.A.

285

172

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Aldose reductase (AR) has been implicated in the etiology of diabetic cataract, as well as in other complications. However, the role of AR in these complications remains controversial because the strongest supporting evidence is drawn from the use of AR inhibitors for which specificity in vivo cannot be ascertained. To settle this issue we developed transgenic mice that overexpress AR in their lens epithelial cells and found that they become susceptible to the development of diabetic and galactose cataracts. When the sorbitol dehydrogenase-deficient mutation is also present in these transgenic mice, greater accumulation of sorbitol and further acceleration of diabetic cataract develop. These genetic studies demonstrated convincingly that accumulation of polyols from the reduction of hexose by AR leads to the formation of sugar cataracts.Diabetic complications such as neuropathy, nephropathy, retinopathy, and cataract, etc., occur in both insulin-dependent and noninsulin-dependent diabetes mellitus. Hyperglycemia has long been suspected as the cause of these manifestations, and the results of the Diabetic Control and Complications Trial (1) appear to confirm it. However, by what mechanism elevated blood glucose leads to these complications is unclear. One theory implicates the polyol pathway as a cause of diabetic cataract because of the discovery of polyols in cataractous lenses (2) and the identification of aldose reductase (AR) that reduces various sugars to their polyols (3, 4). AR reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SorD). Because sorbitol does not readily diffuse out of cells and its oxidation to fructose is slow, the accumulation of sorbitol under the hyperglycemic state would increase the intracellular osmotic pressure, leading to swelling and eventual rupture of the lens fiber cells (5). The involvement of AR in diabetic cataract is supported by the fact that animals such as rats and dogs that have high levels of this enzyme in their lenses are prone to develop diabetic cataract, whereas mice that have low lens AR activity are not (6). Rats and dogs also develop galactose-induced cataracts more readily than diabetes-induced cataracts (7). This fact agrees with the polyol model because galactose is a better substrate than glucose for AR in vitro, and its reduction product galactitol is not further converted to other metabolites, resulting in faster buildup of this polyol. Additional evidence for the polyol model came from the fact that several AR inhibitors could suppress cataract formation in experimentally induced diabetic animals (8-10). However, these drugs may inhibit AR by nonspecific hydrophobic interactions (11,12), and their beneficial effects may be derived from the inhibition of other enzymes. The strongest challenge to the polyol model is the fact that kinetic analyses (13, 14) and x-ray crystallographic studies (15) indicated that AR has a very low affinity for glucose and galactose, and it has not been demonstrated directly that...

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“…17 Tolrestat 18 was developed from alrestatin by means of molecular modification, where the imido ring was cleaved to afford naphthoylglycine derivatives. 17,18 Epalrestat was developed by introducing of the substituent onto the 5-position in rhodanine-N-acetic acid. 19 The isomeric form of epalrestat has been revealed by X-ray crystal analysis; however, epalrestat easily isomerizes in solution even under natural light.…”

Section: Structures and In Vitro Activities Of Potent Inhibitorsmentioning

confidence: 99%

Aldose Reductase Inhibitors

Oka

Kato

2001

Journal of Enzyme Inhibition

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Aldose reductase ([EC1.1.1.21]: AR) acts on the first step of the polyol metabolic pathway to catalyze the reduction of glucose to sorbitol with NADPH as a coenzyme. Hyperactivity of the pathway in individuals with high blood glucose level is closely related to the onset or progression of diabetic complications. AR inhibitors have therefore been noted as possible pharmacotherapeutic agents for the treatment of diabetic complications. One AR inhibitor has been on the market in Japan, while some potent inhibitors are in clinical trials. Reviewed are the physiological roles of AR, the chemical structures of AR inhibitors, interactions of AR inhibitors with AR using X-ray studies, and the following potencies of AR inhibitors: in vitro activities for AR, in vitro selectivities between AR and aldehyde reductase, their pharmacological effects in vivo, and their effectiveness in clinical trials. Also discussed are directions for the design of future AR inhibitors.

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N-[[5-(Trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor

Abstract: Synthetisiert wird auf verschiedene Weise die Carbonsäure (IV), aus der man die Titelverbindung (VIII) erhält.

Cited by 114 publications

References 0 publications

RETRACTED: Synthesis and biological evaluation of [1,2,4]triazino[4,3-a] benzimidazole acetic acid derivatives as selective aldose reductase inhibitors

RETRACTED: Synthesis and biological evaluation of [1,2,4]triazino[4,3-a] benzimidazole acetic acid derivatives as selective aldose reductase inhibitors

Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens.

Aldose Reductase Inhibitors

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