Acetic Acid Aldose Reductase Inhibitors Bearing a Five-Membered Heterocyclic Core with Potent Topical Activity in a Visual Impairment Rat Model

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• 作者：Concettina La Motta ; Stefania Sartini ; Silvia Salerno ; Francesca Simorini ; Sabrina Taliani ; Anna Maria Marini ; Federico Da Settimo ; Luciana Marinelli ; Vittorio Limongelli ; Ettore Novellino
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 12, 2008
• 年：2008
• 卷：51
• 期：11
• 页码：3182 - 3193
• 全文大小：1356K
• 年卷期：v.51,no.11(June 12, 2008)
• ISSN：1520-4804

文摘

A number of 1,2,4-oxadiazol-5-yl-acetic acids and oxazol-4-yl-acetic acids were synthesized and tested for their ability to inhibit aldose reductase (ALR2). The oxadiazole derivatives, 7c, 7f, 7i, and 8h, 8i, proved to be the most active compounds, exhibiting inhibitory levels in the submicromolar range. In this series, the phenyl group turned out to be the preferred substitution pattern, as its lengthening to a benzyl moiety determined a general reduction of the inhibitory potency. The lead compound, 2-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]acetic acid, 7c, showed an excellent in vivo activity, proving to prevent cataract development in severely galactosemic rats when administered as an eye-drop solution in the precorneal region of the animals. Computational studies on the ALR2 inhibitors were performed to rationalize the structure−activity relationships observed and to provide the basis for further structure-guided design of novel ALR2 inhibitors.