Aldose Reductase Inhibitors: An Update

Tsai, Sandra C.; Burnakis, Thomas G.

doi:10.1177/106002809302700616

Cited by 39 publications

(9 citation statements)

References 11 publications

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“…The other two compounds, M-22971, an indan-1-one, and M-45373, bearing a pyrrolo [3,4-d]pyridazin-1-one moiety, were found to have IC 50s < 10 μM (1.8 and 5.8 μM IC 50 , respectively). Furthermore, compounds M-31850 and M-22971 contained scaffolds found in the drugs, Alrestatin [33] and Indacrinone [34], that have been approved for use in humans. Although compound M-22971 has a structure common to bidentate ligands, i.e.…”

Section: Secondary Screen: Validation Of Candidate Inhibitors From Prmentioning

confidence: 99%

High-Throughput Screening for Human Lysosomal β-N-Acetyl Hexosaminidase Inhibitors Acting as Pharmacological Chaperones

Tropak

Blanchard

Withers

et al. 2007

Chemistry & Biology

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The adult forms of Tay-Sachs and Sandhoff diseases result when the activity of beta-hexosaminidase A (Hex) falls below approximately 10% of normal due to decreased transport of the destabilized mutant enzyme to the lysosome. Carbohydrate-based competitive inhibitors of Hex act as pharmacological chaperones (PC) in patient cells, facilitating exit of the enzyme from the endoplasmic reticulum, thereby increasing the mutant Hex protein and activity levels in the lysosome 3- to 6-fold. To identify drug-like PC candidates, we developed a fluorescence-based real-time enzyme assay and screened the Maybridge library of 50,000 compounds for inhibitors of purified Hex. Three structurally distinct micromolar competitive inhibitors, a bisnaphthalimide, nitro-indan-1-one, and pyrrolo[3,4-d]pyridazin-1-one were identified that specifically increased lysosomal Hex protein and activity levels in patient fibroblasts. These results validate screening for inhibitory compounds as an approach to identifying PCs.

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Section: Secondary Screen: Validation Of Candidate Inhibitors From Prmentioning

confidence: 99%

High-Throughput Screening for Human Lysosomal β-N-Acetyl Hexosaminidase Inhibitors Acting as Pharmacological Chaperones

Tropak

Blanchard

Withers

et al. 2007

Chemistry & Biology

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“…Studies on excised rat retinas (Ola, et al, 2006) concluded that glucose metabolism downstream of hexokinase is not elevated by hyperglycemia or diabetes, but that intermediates of alternative glucose metabolism, such as those of the polyol pathway, are increased. In clinical trials, inhibitors of aldose reductase have generally failed to produce the desired results in decreasing the progression of neuropathy, although study data continue to suggest that improvements in the inhibitors and trial design may ultimately produce a therapeutic benefit (Tsai and Burnakis, 1993). …”

mentioning

confidence: 99%

Bioenergetics in diabetic neuropathy: what we need to know

Hinder¹,

Vincent²,

Burant

et al. 2012

J Peripheral Nervous Sys

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Progress in developing treatments for diabetic neuropathy is slowed by our limited understanding of how disturbances in metabolic substrates- glucose and fatty acids- produce nerve injury. In this review, we present the current oxidative stress hypothesis and experimental data that support it. We identify weaknesses in our understanding of diabetes-disordered metabolism in the neurovascular unit; i.e. in critical cell types of the microvascular endothelium, peripheral sensory neurons, and supporting Schwann cells. Greater understanding of peripheral nervous system bioenergetics may provide insight into new drug therapies or improvements in dietary interventions in diabetes or even pre-diabetes.

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“…1). [22][23][24][25][26][27][28] Despite a large number of experimental and clinical studies of different aldose reductase inhibitors (ARIs), their efficacy remains controversial, and their theoretical rationale is consequently disputed.l 29 -35 ] The efficacy of ARls in preventing, halting or reversing diabetic complications should be regarded in relation to the results of euglycaemia to fully appreciate their potential benefits and limitations. Fructose is also a more potent glycating agent than glucose)8] Aldose Reductase Inhibitors Nicotinamide adenine dinucleotides are the cofactors of the polyol pathway, and they intricately link the sorbitol pathway to other metabolic pathways.l9, I 0] Several other biochemical derangements have been hypothesised in the pathogenesis of diabetic complications, such as chronic hypoxia (secondary to vascular abnormalities),111-13] lipid abnormalities, [14] free radical formation [ 15,16] and myoinositol depletion.l 17 -19 ] These derangements may be intricately related to each other, to the biochemical consequences of high glucose levels mentioned above or to other toxic effects of gl ucose.f20, 21] Over the past 10 years, many different compounds have been developed that diminish the flux of glucose through the polyol pathway by inhibition of the key enzyme aldose reductase.…”

Section: Discussionmentioning

confidence: 99%

The Efficacy of Aldose Reductase Inhibitors in the Management of Diabetic Complications

Gerven

Tjon-A-Tsien

1995

Drugs & Aging

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Recently, aldose reductase inhibitors (ARIs) have been registered in several countries for the improvement of glycaemic control. However, their efficacy is still controversial. ARIs inhibit the enhanced flux of glucose through the polyol pathway. As such, they can never be more effective than normoglycaemia, and so their potential benefits and limitations should be considered relative to the effects of prolonged euglycaemia. The clinical effects of ARIs can be put into perspective by assessing the effects of improved glycaemic control attained in randomised trials of intensive insulin treatment [such as the Diabetes Control and Complications Trial (DCCT)] and after pancreatic transplantation. Although direct comparison of these 3 interventions is hampered by differences in patient populations, duration and methods of follow-up and in the potency of ARIs, the effects of these 3 metabolic interventions and their course in time appear remarkably similar. For neuropathy, all 3 interventions induce an increase in average motor nerve conduction velocity of approximately 1 m/sec during the first months of treatment. At the same time, improvement of painful symptoms may occur. These changes probably largely represent a metabolic amelioration of the condition of the nerves. Around the second year of treatment with all 3 forms of metabolic improvement, an acceleration of nerve conduction of a similar magnitude occurs, with signs of structural nerve regeneration and some sensory recuperation. Experience with ARIs in nephropathy is still limited, but similar improvements in glomerular filtration rate and, less consistently, in urinary albumin excretion were found during short term normoglycaemia produced by all 3 forms of treatment. Comparison of a small number of studies, however, shows differences between intensive insulin regimens, pancreatic transplantation and ARIs in effects on retinopathy. Retinopathy often temporarily deteriorates in the early phases of improved glycaemic control, but this is not noted with ARIs. New microaneurysm formation was slightly reduced in a single long term study with the ARI sorbinil, but the preventive effects on the overall levels of retinopathy seemed less strong than in normoglycaemia trials of similar duration. However, the pharmacodynamic effects on inhibiting the polyol pathway differ among ARIs, and the half-life of the inhibiting effect of sorbinil may have been too short for a complete reduction of polyol pathway activity. The trials of prolonged intensive insulin therapy and pancreatic transplantation have demonstrated that very strict metabolic control must be maintained continuously for many years before a significant reduction of complications can be demonstrated.(ABSTRACT TRUNCATED AT 400 WORDS)

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Aldose Reductase Inhibitors: An Update

Cited by 39 publications

References 11 publications

High-Throughput Screening for Human Lysosomal β-N-Acetyl Hexosaminidase Inhibitors Acting as Pharmacological Chaperones

High-Throughput Screening for Human Lysosomal β-N-Acetyl Hexosaminidase Inhibitors Acting as Pharmacological Chaperones

Bioenergetics in diabetic neuropathy: what we need to know

The Efficacy of Aldose Reductase Inhibitors in the Management of Diabetic Complications

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