6,7-Dihydroxy-4-phenylcoumarin as inhibitor of aldose reductase 2.
We report the structure-activity relationship of a series of coumarins as aldose reductase 2 (ALR2) inhibitors and their suppressive effect on the accumulation of galactitol in the rat lens. We evaluated their ALR2 selectivity profile against sorbitol dehydrogenase and aldehyde reductase (ALR1). Our study revealed that substitutions in the C7 OH group enhanced the potency toward ALR2, while the C6 OH group interferes with ALR1 inhibition activity. Having the phenyl moiety at C4 leads to improved potency and improved selectivity. A molecular docking study suggested that 6,7-dihydroxy-4-phenylcoumarin (15) binds to ALR2 in a different manner from epalrestat. Furthermore, compound 15 clearly suppressed galactitol accumulation in a dose-dependent manner. These results provide an insight into the structural requirements of coumarins for developing a new-type of selective ALR2 inhibitor.
Kato
Atsushi
A
Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp
Kobayashi
Kaori
K
Narukawa
Kayo
K
Minoshima
Yuka
Y
Adachi
Isao
I
Hirono
Shuichi
S
Nash
Robert J
RJ
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004376:Galactitol / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D012236:Rhodanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology
C555990:6,7-dihydroxy-4-phenylcoumarin; D003374:Coumarins; D053778:Thiazolidines; D004376:Galactitol; C094411:4-phenylcoumarin; C038131:epalrestat; D012236:Rhodanine; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase