Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
Bioorg Med Chem Lett. 2010 Oct 1;20(19):5630-3. doi: 10.1016/j.bmcl.2010.08.038. Epub 2010 Aug 12.
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.
我们报告了一系列香豆素作为醛糖还原酶 2 (ALR2)抑制剂的结构-活性关系，以及它们对大鼠晶状体中天冬氨酸积累的抑制作用。我们评估了它们对山梨醇脱氢酶和醛还原酶 (ALR1)的 ALR2 选择性特征。我们的研究表明，C7 OH 基团的取代增强了对 ALR2 的效力，而 C6 OH 基团干扰了对 ALR1 抑制活性。在 C4 位具有苯基部分可提高效力和选择性。分子对接研究表明，6,7-二羟基-4-苯基香豆素 (15)与 ALR2 的结合方式与依帕司他不同。此外，化合物 15 明显以剂量依赖的方式抑制半乳糖醇的积累。这些结果为开发新型选择性 ALR2 抑制剂提供了对香豆素结构要求的深入了解。
