On the prodrug potential of novel aldose reductase inhibitors with diphenylmethyleneaminooxycarboxylic acid structure

• Published in: European journal of pharmaceutical sciences Vol. 15; no. 1; pp. 11 - 20
• Main Authors: Rakowitz, Dietmar, Matuszczak, Barbara, Gritsch, Stefan, Hofbauer, Peter, Krassnigg, Andreas, Costantino, Luca
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01-02-2002; Elsevier
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - metabolism; Aldose reductase inhibitors; Analytical, structural and metabolic biochemistry; Animals; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Biological and medical sciences; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Cattle; Diphenylmethyleneaminooxycarboxylic acids; Enzymatic hydrolysis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; General pharmacology; Hydrolysis; Medical sciences; Oxidoreductases; Oxime ethers; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Prodrugs; Prodrugs - chemistry; Prodrugs - pharmacology; Structure-Activity Relationship; Diphenylmethyleneaminooxycarboxylic acids; Aldose reductase inhibitors; Prodrugs; Oxime ethers; Enzymatic hydrolysis; Hydrolysis; Ether; Enzyme; Carboxylic acid; Aldehyde reductase; Enzymatic digestion; Enzyme inhibitor; Oxime; Oxidoreductases; Prodrug; Chemical synthesis
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/S0928-0987(01)00192-0

Diphenylmethyleneaminooxycarboxylic acids were found to represent novel type inhibitors of the enzyme aldose reductase. Ester derivatives of the most active compound (
3c) (IC
50=33 μM) were prepared as potential prodrugs and the rate of degradation was studied by treatment with buffers, plasma, and various hydrolytic enzymes. Whereas all compounds were not hydrolysed at physiological pH, incubation in the presence of enzyme led to hydrolysis. The rate of enzymatic degradation, however, depended on the nature of the ester function. Whereas the isopropyl ester (
4) turned out to be the most stable compound, the ethyl ester (
2c) could be cleaved in the presence of esterase and lipase, respectively. The benzylic and aromatic esters were found to be hydrolysed rapidly in the presence of lipase (benzyl ester,
7), or in plasma, by cholinesterase and esterase (phenyl ester,
6), respectively.