A Novel Carboxymethylated Mercaptotriazinoindole Inhibitor of Aldose Reductase Interferes With the Polyol Pathway in Streptozotocin-Induced Diabetic Rats

Prnová, Marta Šoltésová; Ballekova, Jana; Gajdošíková, A.; Gajdosík, A; Štefek, Milan

doi:10.33549/physiolres.933034

Cited by 16 publications

(29 citation statements)

References 15 publications

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“…No signs or symptoms of cemtirestat toxicity developed during the 120-day treatment period. These observations are in accordance with our previously reported findings that revealed no acute toxicological manifestation of cemtirestat administered intragastrically (50 mg/kg/day) to male Wistar rats for five consecutive days (Soltesova Prnova et al 2015a).…”

Section: Animal Studiessupporting

confidence: 93%

General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

Prnová

Račková

Kovacikova

et al. 2019

Interdisciplinary Toxicology

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Cemtirestat, 3-mercapto-5H-[1,2,4]-triazino[5,6-b]indole-5-acetic acid was recently designed and patented as a highly selective and efficient aldose reductase inhibitor endowed with antioxidant activity. The aim of the present study was to assess the general toxicity of cemtirestat using in silico predictions, in vitro and in vivo assays. ProTox-II toxicity prediction software gave 17 “Inactive” outputs, a mild hepatotoxicity score (0.52 probability) along with a predicted LD50 of 1000 mg/kg. Five different cell lines were used including the immortalized mouse microglia BV-2, the primary human fibroblasts VH10, the insulinoma pancreatic β-cells INS-1E, the human colon cancer cells HCT116 and the human immortalized epithelial endometrial cell lines HIEEC. In contrast to the clinically used epalrestat, cemtirestat showed remarkably low cytotoxicity in several different cell culture viability tests such as MTT proliferation assay, neutral red uptake, BrdU incorporation, WST-1 proliferation assay and propidium iodide staining followed by flow cytometry. In a yeast spotting assay, the presence of cemtirestat in incubation of Saccaromyces cerevisiae at concentrations as high as 1000 µM did not affect cell growth rate significantly. In the 120-day repeated oral toxicity study in male Wistar rats with daily cemtirestat dose of 6.4 mg/kg, no significant behavioral alterations or toxicological manifestations were observed in clinical and pathological examinations or in hematological parameters. In summary, these results suggest that cemtirestat is a safe drug that can proceed beyond preclinical studies.

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Section: Animal Studiessupporting

confidence: 93%

General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

Prnová

Račková

Kovacikova

et al. 2019

Interdisciplinary Toxicology

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“…Chemistry. A commercially available compound, 2-(3thioxo-2H- [1,2,4]triazino [5,6-b]indol-5(3H)-yl)acetic acid (4) [CAS: 309283-89-4], recently identified as an ALR2 inhibitor 1 and reported also under the designation of cemtirestat, 3,6 is to our knowledge devoid of any literature report on its chemical synthesis. 7 Therefore, we developed a procedure for its Values of total energies, calculated as described in the experimental section, related by subtraction to the most stable tautomer in a given environment.…”

Section: ■ Resultsmentioning

confidence: 99%

“…In our previous study, carboxymethylated thioxotriazinoindoles were identified as AR inhibitors with high efficacy and selectivity. 1 Among the novel compounds, 2-(3-thioxo-2H- [1,2,4]triazino [5,6-b]indol-5(3H)-yl)acetic acid (4) (cemtirestat, CMTI, Figures 1 and 3) was found the most promising inhibitor endowed also with antioxidant activity. 2,3 Considering excellent "lead-likeness" of cemtirestat (4), we proceeded with optimization of its thioxotriazinoindole scaffold by replacement of sulfur with oxygen, with the aim to improve the inhibitory efficacy and selectivity.…”

Section: ■ Introductionmentioning

confidence: 99%

Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity

et al. 2019

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Inhibition of aldose reductase (AR), the first enzyme of the polyol pathway, is a promising approach in treatment of diabetic complications. We proceeded with optimization of the thioxotriazinoindole scaffold of the novel AR inhibitor cemtirestat by replacement of sulfur with oxygen. A series of 2-(3-oxo-2H-[1,2,4]triazino [5,6-b]indol-5(3H)-yl)acetic acid derivatives (OTIs), designed by molecular modeling and docking, were synthesized. More electronegative and less bulky oxygen of OTIs compared to the sulfur of the original thioxotriazinoindole congeners was found to form a stronger Hbond with Leu300 of AR and to render larger rotational flexibility of the carboxymethyl pharmacophore. AR inhibitory activities of the novel compounds were characterized by the IC 50 values in a submicromolar range. Markedly enhanced inhibition selectivity relative to the structurally related aldehyde reductase was recorded. To conclude, structure modification of the original carboxymethylated thioxotriazinoindole cemtirestat by isosteric replacement of sulfur with oxygen in combination with variable N(2) simple substituents provided novel analogues with increased AR inhibition efficacy and markedly improved selectivity.

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“…The enzyme aldo-keto reductase (AR) determines the overall rate of the polyol pathway, and it also has a low affinity (K m > 100 mM) for glucose while in nondiabetic subjects, wherein the glucose concentration is normal. During the metabolism of glucose by the polyol pathway, a very minute percentage of total glucose is used [67,69]. In a hyperglycemic state, AR activation is achieved by increased intracellular glucose.…”

Section: Increased Intracellular Formation Of Advanced Glycationmentioning

confidence: 99%

Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review

Unuofin

Lebelo

2020

Oxidative Medicine and Cellular Longevity

161

114

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Diabetes mellitus is a metabolic disorder that majorly affects the endocrine gland, and it is symbolized by hyperglycemia and glucose intolerance owing to deficient insulin secretory responses and beta cell dysfunction. This ailment affects as many as 451 million people worldwide, and it is also one of the leading causes of death. In spite of the immense advances made in the development of orthodox antidiabetic drugs, these drugs are often considered not successful for the management and treatment of T2DM due to the myriad side effects associated with them. Thus, the exploration of medicinal herbs and natural products as therapeutic sources for the treatment of T2DM is promoted because they have little or no side effects. Bioactive molecules isolated from natural sources have been proven to lower blood glucose levels via regulating one or more of the following mechanisms: improvement of beta cell function, insulin resistance, glucose (re)absorption, and glucagon-like peptide-1 homeostasis. In recent times, the mechanisms of action of different bioactive molecules with antidiabetic properties and phytochemistry are gaining a lot of attention in the area of drug discovery. This review article presents an update of the findings from clinical research into medicinal plant therapy for T2DM.

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A Novel Carboxymethylated Mercaptotriazinoindole Inhibitor of Aldose Reductase Interferes With the Polyol Pathway in Streptozotocin-Induced Diabetic Rats

Cited by 16 publications

References 15 publications

General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity

Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review

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