6,7-Dihydroxy-4-phenylcoumarin as inhibitor of aldose reductase 2

doi:10.1016/j.bmcl.2010.08.038

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 19, 1 October 2010, Pages 5630-5633

https://doi.org/10.1016/j.bmcl.2010.08.038 Get rights and content

Abstract

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.

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6,7-Dihydroxy-4-phenylcoumarin as inhibitor of aldose reductase 2

Abstract

Graphical abstract

FEBS Lett.

Biochem. Pharmacol.

J. Biol. Chem.

Exp. Eye Res.

Exp. Diabetes Res.

Curr. Med. Chem.

Biochem. J.

Science

Diabetes

Diabetes

Kidney Int.