On the prodrug potential of novel aldose reductase inhibitors with diphenylmethyleneaminooxycarboxylic acid structure.
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 microM) 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.
Rakowitz
Dietmar
D
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria. dietmar.rakowitz@uibk.ac.at
Matuszczak
Barbara
B
Gritsch
Stefan
S
Hofbauer
Peter
P
Krassnigg
Andreas
A
Costantino
Luca
L
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006868:Hydrolysis; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001559:Benzhydryl Compounds; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D011355:Prodrugs; D000449:Aldehyde Reductase