rhodanine and Diabetes-Mellitus

Epalrestat is the only aldose reductase inhibitor that is currently available for diabetic peripheral neuropathy. Oxidative stress impairs endothelial cells, thereby leading to numerous pathological conditions. Increasing antioxidative ability is important to prevent cellular toxicity induced by reactive oxygen species. Epalrestat increases antioxidant defense factors such as glutathione and γ-glutamylcysteine ligase in vascular endothelial cells through activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This increases suppression of oxidative stress-induced cellular toxicity. Cadmium is an industrial and environmental pollutant that targets the vascular endothelium. The vascular system is critically affected by cadmium toxicity. Therapeutic treatment against cadmium toxicity is chelation therapy that promotes metal excretion; however, cadmium chelators can cause renal toxicity. Therefore, safe and efficient therapeutic agents are required. Epalrestat suppresses cadmium-induced cytotoxicity in vascular endothelial cells through activation of Nrf2. In addition, epalrestat affects the intracellular levels of cadmium, cadmium transporter Zrt-Irt-like protein 8 (ZIP8), and metallothionein (MT). The upregulation of ZIP8 and MT may be involved in the suppression of cadmium-induced cytotoxicity by epalrestat. Drug repurposing is a new strategy for drug discovery in which the pharmacological action of existing medicines whose safety and pharmacokinetics have already been confirmed clinically and whose use has been approved is examined comprehensively at the molecular level. The results can be applied to the development of existing drugs for use as medicines for the treatment of other diseases. This review provides useful findings for future expansion of indications as research leading to drug repurposing of epalrestat.

Topics: Aldehyde Reductase; Antioxidants; Cadmium; Chelating Agents; Diabetes Mellitus; Diabetic Neuropathies; Endothelial Cells; Environmental Pollutants; Glutathione; Humans; Ligases; Metallothionein; NF-E2-Related Factor 2; Reactive Oxygen Species; Rhodanine; Thiazolidines

At present, diseases resulting from various reasons have been causing deadly fears to humans and previously incogitable losses to health. Meanwhile, the patient compliance has been weakening because of drug resistance and serious drug adverse effects. There is therefore an urgent need for the development of novel structural agents. Rhodanine derivatives have exhibited wide biological activities, as well as significant industrial applications, which suggests that rhodanine heterocycle represents a key structural motif in heterocyclic chemistry and occupies a prominent position in drug discovery. Here, we review some deadly defects of clinical medicines to the therapy of diseases and important advances on rhodanine derivatives in drug researches (e.g. as anti-diabetic, anti-viral, antiinflammatory, anti-microbial, anti-tumor agents and inhibitors for Alzheimer Disease), indicating that rhodanine heterocycle could be used as a significant pharmacophore to develop novel pharmacological active molecules. It is believed that the review is of importance for new ideas in the development of and rational designs of rhodanine-based drugs.

Topics: Alzheimer Disease; Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Diabetes Mellitus; Drug Design; Humans; Hypoglycemic Agents; Neoplasms; Rhodanine

Topics: Aldehyde Reductase; Arteriosclerosis; Blood Glucose; Diabetes Mellitus; Enzyme Inhibitors; Guanidines; Humans; Hypoglycemic Agents; Insulin Resistance; Rhodanine; Thiazolidines

Topics: Aldehyde Reductase; Animals; Binding Sites; Blood Glucose; Cataract; Chemical Phenomena; Chemistry; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Fluorenes; Galactose; Humans; Hydantoins; Imidazoles; Imidazolidines; Models, Molecular; Naphthalenes; Phthalazines; Rhodanine; Sorbitol; Structure-Activity Relationship; Substrate Specificity; Sugar Alcohol Dehydrogenases; Thiazolidines; Tissue Distribution

In order to study a long-term effect along with adverse action of epalrestat, an aldose reductase inhibitor, a randomized, prospective study was conducted over the period of 3 years at 112 facilities. Six hundred and three diabetic patients with median motor conduction velocity (MCV)>40 m/s, HbA1c<9% were randomly allocated to epalrestat (50 mg/day p.o. ac, t.i.d.) group (E group: n=289, age: 61+/-9.8 y.o.) and a control group (C group: n=305, age: 61+/-9.1 y.o.). MCV was measured once a year for 3 years. MCV (m/s, M+/-S.D.) on baseline, 1 year and 3 years, was 52.0+/-4.5, 52.2+/-4.9, 52.1+/-4.6 in E group and 53.3+/-4.4, 52.4+/-4.2, 52.0+/-4.6 in C group, respectively. After 3 years, difference from the baseline was significant (p<0.0001, E versus C). Among the subjects with HbA1c<7.0%, C group showed marked deterioration of MCV while in E group, there was no significant deterioration (p<0.001). Although, the subjects with pre-proliferative or proliferative retinopathy, there was no difference between E and C groups for 3 years, in subjects with background retinopathy or without retinopathy, deterioration rate of E group was significantly less than that of C group (p<0.0001). Epalrestat was found to prevent deterioration of MCV especially in well-controlled patients without advanced complications. No remarkable side effects serious enough to discontinue the study was observed.

Topics: Age of Onset; Aged; Aldehyde Reductase; Body Mass Index; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Motor Neurons; Neural Conduction; Prospective Studies; Rhodanine; Thiazolidines

Topics: Action Potentials; Aldehyde Reductase; Diabetes Mellitus; Diabetic Neuropathies; Double-Blind Method; Electric Stimulation; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neural Conduction; Reaction Time; Rhodanine; Thiazolidines

While the mechanism in the pathogenesis of diabetic corneal disease is unclear, aldose reductase has been implicated in corneal disease. The effects of an oral aldose reductase inhibitor (ARI) on the ocular surface of diabetic patients after cataract surgery were studied.. This clinical trial was designed to be randomised, double blinded, and placebo controlled. Pseudophakic patients with diabetes were randomly assigned to treatment with either oral ARI (ONO-2235) (n=12) or placebo (n=9) for 12 weeks. The vital staining of the ocular surface, tear production and clearance, break up time in tears (BUT), corneal and conjunctival sensation, and symptom score before treatments were examined as well as 4, 8, 12 weeks after the administration. Specular microscopic evaluation was also performed.. After a 12 week period of oral ARI administration, fluorescein staining scores (from 2.04 (SD 1.12) to 1.46 (1.18); p=0.016), conjunctival sensation (from 1.15 (0.37) to 1.36 (0.31); p=0.0006), and symptom scores (from 5.38 (1.932) to 4.00 (2.07); p=0.0002) recovered significantly. Fluorescein staining of oral ARI administration also decreased compared with placebo (p=0.017). Rose bengal staining, tear clearance, and corneal sensation were improved although this increase was minor. Tear production, BUT, and specular microscopic evaluation of the corneal epithelium and endothelium did not demonstrate a significant change.. Oral ARI opposes the ocular surface changes caused by diabetes, by recovery of ocular surface sensitivity as demonstrated through an improvement in vital staining.

Topics: Administration, Oral; Aged; Aldehyde Reductase; Cataract Extraction; Conjunctiva; Diabetes Mellitus; Double-Blind Method; Enzyme Inhibitors; Epithelium, Corneal; Female; Fluorescein; Fluorescent Dyes; Humans; Male; Microscopy, Fluorescence; Postoperative Period; Rhodanine; Rose Bengal; Sensation; Tears; Thiazolidines

The mechanism in the pathogenesis of diabetic corneal disease is unclear, but aldose reductase may be involved in the corneal disease. We studied the effects of an aldose reductase inhibitor (ARI) on the ocular surface of diabetic patients. Fourteen aphakic or pseudophakic patients with diabetes were treated with orally administered ONO-2235 (150 mg/day). Corneal sensation, vital staining of ocular surface, and tear production were examined before and 3 months after the administration. After a 3-month period of oral ARI, corneal sensation recovered significantly (from 4.1 +/- 4.8 to 3.0 +/- 3.1 g/mm2; p = 0.015), with parallel improvements in rose bengal and fluorescein staining scores (p < 0.05). Tear break-up time had also improved (p = 0.003). Results of Schirmer's test (p = 0.03) and the cotton-thread test (p = 0.0001) showed significant improvement in tear production. Improvement in the dynamics of tear production may be due to an improvement in corneal sensitivity. An oral ARI can improve corneal epithelial changes caused by diabetes, probably through recovery of corneal sensation and tear production.

Topics: Administration, Oral; Aged; Aldehyde Reductase; Cornea; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Rhodanine; Sensation; Tears; Thiazolidines

Aldose reductase (ALR) enzyme plays a significant role in conversion of excess amount of glucose into sorbitol in diabetic condition, inhibitors of which decrease the secondary complication of diabetes mellitus. To understand the structural interaction of inhibitors with ALR enzyme and develop more effective ALR inhibitors, a series of substituted 5-phenylbenzoate containing N-substituted rhodanine derivatives were synthesized and evaluated for their in vitro ALR inhibitory activity. Docking studies of these compounds were carried out, which revealed that the 5-phenylbenzoate moiety deeply influenced the key π-π stacking while 4-oxo-2-thioxothiazolidines contributed in hydrogen bond interactions. The phenyl ring of benzylidene system occupied in specific pocket constituted from Phe115, Phe122, Leu300 and Cys303 while the rhodanine ring forms a tight net of hydrogen bond with Val47 at anionic binding site of the enzyme. The structural insights obtained from the docking study gave better understanding of rhodanine and macromolecular interaction and will help us in further designing and improving of ALR inhibitory activity of rhodanine analogs.

Topics: Aldehyde Reductase; Diabetes Mellitus; Enzyme Inhibitors; Humans; Molecular Docking Simulation; Rhodanine

The synthesis of a series of novel dispiropyrrolidines has been accomplished by 1,3-dipolar cycloaddition reaction with 5-arylidene-1,3-thiazolidine-2,4-dione and 5-arylidene-4-thioxo-1,3-thiazolidine-2-one derivatives as dipolarophiles. The structure and stereochemistry of the cycloadduct have been established by single crystal X-ray structure and spectroscopic techniques. Molecular docking studies were performed on 1FM9 protein. The synthesized compounds were screened for their antidiabetic activity on male Wistar rats.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Drug Design; Humans; Hypoglycemic Agents; Insulin; Ligands; Male; Models, Molecular; Molecular Conformation; Pyrrolidines; Rats; Rats, Wistar; Rhodanine; Thiazolidines

We examined the effect of fidarestat on the increase in sorbitol content in erythrocytes from healthy volunteers in vitro. Fidarestat inhibited the increase with an IC50 value of 18 nmol/l. A subsequent experiment showed that fidarestat had a similar inhibitory effect on the increase in sorbitol content in erythrocytes from diabetic patients. On the other hand, epalrestat, the only aldose reductase inhibitor used clinically, inhibited increase in sorbitol content at a concentration over 500-fold higher than fidarestat. Although the IC50 value of fidarestat was not affected by fasting plasma glucose, HbA1C, age, aldose reductase content or gender, there was a significant positive relationship between the IC50 value of epalrestat and fasting plasma glucose. In addition, in fidarestat (0.25-2 mg/kg)-treated diabetic rats, the inhibitory rate for erythrocyte sorbitol accumulation was well correlated with that for nerve sorbitol accumulation, which indicates that erythrocyte sorbitol is available for assessing the state of sorbitol pathway flux in target tissue after fidarestat administration. These results suggest that fidarestat potently inhibits the increase in sorbitol pathway flux in diabetic patients independent of various factors and that erythrocyte sorbitol is useful for its estimation.

Topics: Age Factors; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Enzyme Inhibitors; Erythrocytes; Fasting; Female; Glycated Hemoglobin; Humans; Imidazoles; Imidazolidines; Male; Rats; Rats, Sprague-Dawley; Rhodanine; Sciatic Nerve; Sex Factors; Sorbitol; Thiazolidines

The effects of a high-glucose medium, insulin, and an aldose reductase inhibitor (ONO-2235) on sorbitol accumulation were compared in the human erythrocyte and the rabbit retina, while the effects of epinephrine on in vitro sorbitol accumulation were investigated in the human and rabbit retina. In both erythrocytes and the retina, linear increments of sorbitol accumulation were observed in a dose-dependent manner with 5 to 50 mM glucose. These increments were markedly inhibited by 100 microM ONO-2235 but not by insulin (400 microU/ml). In the presence of 5 mM glucose, a dose-dependent increase of the sorbitol content of the rabbit retina was seen following epinephrine stimulation (0.4-4.0 microM and this was markedly reduced by 100 microM ONO-2235. Moreover, both 50 mM glucose and 4.0 microM epinephrine increased the sorbitol content of the retina from a diabetic patient, and the glucose-induced increment in sorbitol was significantly reduced by 100 microM ONO-2235. Our data suggested that aldose reductase inhibitors might be useful for the treatment of diabetic retinopathy, since the polyol pathway appears to be an important factor in its pathogenesis, and that catecholamines might have some role in the activation of the retinal polyol pathway.

Topics: Aged; Aldehyde Reductase; Animals; Diabetes Mellitus; Epinephrine; Erythrocytes; Fructose; Glucose; Humans; In Vitro Techniques; Insulin; Male; Rabbits; Reference Values; Retina; Rhodanine; Sorbitol; Thiazolidines

The mechanism by which hyperglycaemia leads to diabetic complications has not been fully elucidated. Non-enzymatic glycosylation leads to considerable functional and structural alteration of proteins. Hyperglycaemia also induces changes in intracellular metabolites, particularly in the polyol pathway. Aldose reductase inhibitors, which block the polyol pathway, have been shown to prevent complications in animal models, and this provides the rationale for the large scale trials that are presently being conducted.

Topics: Aldehyde Reductase; Diabetes Complications; Diabetes Mellitus; Glycolysis; Glycosylation; Humans; Hyperglycemia; Imidazoles; Imidazolidines; Naphthalenes; Phthalazines; Rhodanine; Thiazolidines