Medicinal chemistry of aldose reductase inhibitors

Larson, Eric R.; Lipinski, Christopher A.; Sarges, Reinhard

doi:10.1002/med.2610080202

Cited by 43 publications

(29 citation statements)

References 97 publications

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“…The crystallographic structures of the porcine and human aldose reductase are similar and consist of a single domain folded into an eight-stranded / barrel (Rondeau et al, 1992;Wilson et al, 1992). Although the normal physiological role of aldose reductase has not yet been established, this enzyme is part of the polyol pathway and its action seems to be linked to the development of long-term complications of diabetes mellitus such as cataracts, retinopathy and neuropathy (Larson et al, 1988). Therefore, the design of inhibitors is of great interest and structural information about the active site is helpful in the search for more ef®cient molecules.…”

Section: Introductionmentioning

confidence: 99%

Production of crystals of human aldose reductase with very high resolution diffraction

Lamour

Barth

Rogniaux

et al. 1999

Acta Crystallogr D Biol Cryst

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# 1999 International Union of Crystallography Printed in Denmark ± all rights reserved As the action of human aldose reductase (hAR) is thought to be linked to the pathogenesis of diabetic complications, much effort has been directed towards the analysis of the catalytic mechanism and the development of speci®c inhibitors. Here, the crystallization of recombinant hAR with its cofactor NADP + at 277 K in the presence of the precipitating agent PEG 6000 is reported. The crystals diffract to high resolution (1.1 A Ê ) and belong to the P2 1 space group with unit-cell parameters a = 49.97, b = 67.14, c = 48.02 A Ê , = 92.2 with one molecule per asymmetric unit. Seleno-substituted hAR crystals were also produced and diffract to 1.7 A Ê on a conventional X-ray source.

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Section: Introductionmentioning

confidence: 99%

Production of crystals of human aldose reductase with very high resolution diffraction

Lamour

Barth

Rogniaux

et al. 1999

Acta Crystallogr D Biol Cryst

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“…1,2) Among the members of this superfamily, aldose reductase (AR) is most extensively studied, because the human enzyme, named AKR1B1 in the family, is the first enzyme of the polyol pathway metabolizing glucose into sorbitol and implicated in the chronic complications of diabetes such as retinopathy, neuropathy and nephropathy. 3,4) To prevent/combat diabetes complications arising from undesired activity of this enzyme, a wide range of potential AR inhibitors (ARIs) for human AR were developed. [5][6][7][8] Most inhibitors of AR can be classified into the following three groups: carboxylic acids such as tolrestat and zopolrestat, cyclic imides such as minalrestat and fidarestat, and flavonoids such as quercetin and myricetin.…”

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confidence: 99%

Selective Inhibition of the Tumor Marker AKR1B10 by Antiinflammatory N-Phenylanthranilic Acids and Glycyrrhetic Acid

Endo

Matsunaga

Soda

et al. 2010

Biological & Pharmaceutical Bulletin

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A human aldose reductase-like protein, AKR1B10 in the aldo-keto reductase (AKR) superfamily, was recently identified as a tumor marker of several types of cancer. Tolrestat, an aldose reductase inhibitor (ARI), is known to be the most potent inhibitor of the enzyme. In this study, we compared the inhibitory effects of other ARIs including flavonoids on AKR1B10 and aldose reductase to evaluate their specificity. However, ARIs showed lower inhibitory potency for AKR1B10 than for aldose reductase. In the search for potent and selective inhibitors of AKR1B10 from other drugs used clinically, we found that non-steroidal antiinflammatory N-phenylanthranilic acids, diclofenac and glycyrrhetic acid competitively inhibited AKR1B10, showing K i values of 0.35-2.9 m mM and high selectivity to this enzyme (43-57 fold versus aldose reductase). Molecular docking studies of mefenamic acid and glycyrrhetic acid in the AKR1B10-nicotinamide adenine dinucleotide phosphate (NADP ؉ ؉ ) complex and site-directed mutagenesis of the putative binding residues suggest that the side chain of Val301 and a hydrogen-bonding network among residues Val301, Gln114 and Ser304 are important for determining the inhibitory potency and selectivity of the non-steroidal antiinflammatory drugs. Thus, the potent and selective inhibition may be related to the cancer chemopreventive roles of the drugs, and their structural features may facilitate the design of new anti-cancer agents targeting AKR1B10.

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“…Due to its ability to reduce excess D-glucose into D-sorbitol in non-insulin-dependent tissues (27,28), the enzyme is believed to be of primary importance in the development of severe degenerative complications of diabetes mellitus. AR has one subunit of 315 residues and includes 6 Trp residues.…”

Section: Resultsmentioning

confidence: 99%

Structural Features of Proteins Responsible for Resistance of Tryptophan Residues to Nitrosylation

Suntsova

Nedospasov

2002

IUBMB Life

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Medicinal chemistry of aldose reductase inhibitors

Cited by 43 publications

References 97 publications

Production of crystals of human aldose reductase with very high resolution diffraction

Production of crystals of human aldose reductase with very high resolution diffraction

Selective Inhibition of the Tumor Marker AKR1B10 by Antiinflammatory N-Phenylanthranilic Acids and Glycyrrhetic Acid

Structural Features of Proteins Responsible for Resistance of Tryptophan Residues to Nitrosylation

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