Synthesis of 3-aminorhodanine derivatives as aldose reductase inhibitors

A number of 5-condensated 3-acylaminorhodanines 3 was prepared as potential inhibitors of the aldose reductase by acylation of the amino group of 3-aminorhodanine 1 and subsequent condensation of the 5-methylene function with appropriate aldehydes. Some of these compounds displayed interesting activity.     

Studies on aldose reductase inhibitors from natural products. IV. Constituents and aldose reductase inhibitory effect of Chrysanthemum morifolium, Bixa orellana and Ipomoea batatas.

The hot water extracts of Chrysanthemum morifolium, Bixa orellana and Ipomoea batatas, were found to have potent inhibitory activity towards lens aldose reductase (AR). Ellagic acid (4) was isolated from C. morifolium and I. batatas, isoscutellarein (7) from B. orellana and 3,5-dicaffeoylquinic acid (10) from I. batatas, respectively, as potent inhibitors.     

A series of diarylsubstituted oximes as potential substrate for new aldose reductase inhibitors

In the course of our research aimed at the discovery of new compounds acting as aldose reductase inhibitors, we tested a series of some (E)‐ and (Z)‐ω‐[[(aryldiazinylmethylene)amino]oxy]alkanoic acids, which were found to have moderate in vitro inhibitory activity. On this basis we have now prepared several new derivatives modified both at the length of the chain and at its terminal carboxylic group, together with compounds carrying various substituents at the phenyl ring. This paper describes their synthesis and biological properties.     

Development of a practical synthesis of novel, pyrrole-based HMG-CoA reductase inhibitors

This paper describes the development of an efficient and scalable second generation synthesis of novel, pyrrole-based HMG-CoA reductase inhibitors. Compound 1 was identified as part of a discovery program aimed at finding improved treatments for hypercholesterolemia. Herein, we describe an efficient synthesis of its highly functionalized pyrrole core followed by attachment of the 3,5-dihydroxyhexanoic acid side chain via ylide olefination chemistry.     

Diastereoisomeric derivatization and liquid chromatographic analysis of N-(phenylsulfonyl)-2-phenylglycine aldose reductase inhibitors

A series of (S)- and (R)-N-(phenylsulfonyl)-2-phenylglycines are synthesized as potential inhibitors of the enzyme aldose reductase. In vitro analysis of these compounds reveals that the S-enantiomers are more potent than the corresponding R-enantiomers and that the difference in potencies between enantiomeric pairs is dependent on the nature of the ring substituent. To ensure that the enantioselectivity observed does not reflect varying degrees of racemization during the synthesis of the N-(phenylsulfonyl)-2-phenylglycines, the enantiomeric purity of these products is determined by HPLC after chiral derivatization. Each 2-phenylglycine inhibitor is derivatized with R-alpha-methylbenzylamine, and the resulting diastereomers are analyzed using reversed and normal achiral stationary phases. Reversed-phase methods with C18 or phenyl stationary phases and solvent mixtures of acetonitrile or methanol in water do not provide satisfactory resolution of the diastereomers. However, normal-phase analyses with a silica stationary phase and mixtures of methanol, ethanol, or acetonitrile in chloroform provide good separations with relatively short analysis times. The normal-phase analyses demonstrate that a single diastereomeric amide forms from each N-(phenylsulfonyl)-2-phenylglycine product, establishing that these compounds do not racemize during synthesis.     

姜黄素及其衍生物对醛糖还原酶的抑制作用

高血糖条件下,多元醇代谢通路（图1）被激活是糖尿病并发症发生与发展的重要原因之一。     

Studies on aldose reductase inhibitors from medicinal plant of "sinfito," Potentilla candicans, and further synthesis of their related compounds

For several years we have screened natural products having aldose reductase (AR) inhibitory activity. 3,3',4-Tri-O-methylellagic acid 4'-sulfate potassium salt (2) was isolated from a Mexican herb "Sinfito" (Potentilla candicans) as a potent AR inhibitory active constituent. 2 was more potent (IC50 = 8.0 x 10(-8)M) than ellagic acid, which is one of the natural inhibitors of AR. So we examined the synthesis of ellagic acid derivatives and found that the sulfate group is one of the important function.     

Synthesis and activity of a new series of (Z)-3-phenyl-2-benzoylpropenoic acid derivatives as aldose reductase inhibitors

During the course of studies directed towards the discovery of novel aldose reductase inhibitors for the treatment of diabetic complications, we synthesized a series of new (Z)-3-phenyl-2-benzoylpropenoic acid derivatives and tested their in vitro inhibitory activities on rat lens aldose reductase. Of these compounds, (Z)-3-(3,4-dihydroxyphenyl)-2-(4-methylbenzoyl)propenoicacid (3k) was identified as the most potent inhibitor, with an IC50 of 0.49 microM. The theoretical binding mode of 3k was obtained by simulation of its docking into the active site of the human aldose reductase crystal structure.     

Synthesis and aldose reductase inhibitory activities of benzyl 2-oxazolecarbamate analogues.

Various analogues of benzyl 5-phenyl-2-oxazolecarbamate (1a) were synthesized, and the structure-activity relationship of these analogues as aldose reductase inhibitor was studied. The carbamate group was necessary for the inhibitory activity. The introduction of an alkyl group at the C-4 position of 1a enhanced the inhibitory activity, however, the N-carboxymethyl group on the carbamate moiety counteracted to a hydrophobic interaction between the alkyl group at the C-4 position and the enzyme molecule.     

Predicting the binding mode of known NCp7 inhibitors to facilitate the design of novel modulators

The HIV-1 nucleocapsid protein (NCp7) is an emerging target for antiretroviral therapy. Five hits have been reported to inhibit the NCp7-viral nucleic acids interaction at micromolar concentrations. We used two computationally refined structures of NCp7 as receptors to propose a reliable binding pose for these compounds, by means of computational methods. Theoretical binding modes are in agreement with available experimental data. Results lay the foundations for a rationale development of more effective NCp7 inhibitors.     

Capillary gas chromatographic-electron-capture assay for the aldose reductase inhibitor imirestat in lens and plasma

A sensitive and selective gas chromatographic-electron-capture assay was developed for the determination of the aldose reductase inhibitor imirestat in lens and plasma. The method involves solid-phase extraction of drug and internal standard from the plasma specimen or lens sample homogenate using "Baker"-10 SPE extraction columns followed by derivatization with pentafluorobenzyl bromide and further purification. Derivatives of drug and internal standard were separated on a fused-silica capillary column and analyzed using a 63Ni electron-capture detector. The limit of detection was 2.5 ng per lens or ml of plasma. The method was used to evaluate the pharmacokinetics of imirestat in human subjects and to quantitate imirestat in animal lens tissue following topical ocular administration.     

Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia

Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of coronary artery disease, stroke, and overall mortality. Statins are hypolipemic drugs that are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in liver by competitive inhibition regarding the substrate or molecular target HMG-CoA reductase. We have herewith used computer-aided molecular design tools, i.e., flexible docking, virtual screening in large data bases, molecular interaction fields to propose novel potential HMG-CoA reductase inhibitors that are promising for the treatment of hypercholesterolemia.     

Synthesis and aldose reductase inhibitory activity of triazine derivatives possessing acetic acid group.

N-Acetic acid derivatives of 6-aryl-pyrazolo-triazin-4-ones were synthesized for evaluation as new aldose reductase inhibitors. The intrinsic activity of each compound was assessed by measuring the inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All the prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10(-6) M less than or equal to IC50 less than or equal to 10(-4) M). Furthermore, biological activity (log 1/IC50) for most of the data sets could be correlated directly to electronic and steric parameters. Finally, spatial configuration of the most active derivative 6c (IC50 = 2 x 10(-6) M) was compared with that of tolrestat and with pharmacophor requirements of the aldose reductase inhibitor site using a molecular modeling system.