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新型吲哚基双功能醛糖还原酶抑制剂/抗氧化剂的开发：用于治疗糖尿病并发症的有前途的药物。

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications.

机构信息

Institute of Experimental Pharmacology and Toxicology, CEM SAS, Dúbravská Cesta 9, 841 04 Bratislava, Slovakia.

Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15 Bratislava, Slovakia.

出版信息

Molecules. 2021 May 12;26(10):2867. doi: 10.3390/molecules26102867.

DOI:10.3390/molecules26102867
PMID:34066081
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8151378/
Abstract

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure-activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of 'drug-likeness". Novel promising structures of putative multifunctional ARIs/AOs are designed.

摘要

醛糖还原酶（AR，ALR2）是多元醇途径的第一个酶，与糖尿病并发症的病理生理学有关。因此，醛糖还原酶抑制剂（ARIs）为治疗多种糖尿病并发症提供了一种有希望的治疗方法。此外，ARIs 在治疗慢性炎症相关疾病和几种遗传代谢疾病方面的治疗潜力最近也得到了证实。取代吲哚是一组具有多种生物学活性的有趣化合物。本文综述了近年来开发的一系列基于吲哚的双功能醛糖还原酶抑制剂/抗氧化剂（ARIs/AOs）。介绍了在糖尿病并发症的体外、离体和体内模型中获得的实验结果。讨论了关于羧甲基药效团区域异构体和核心支架修饰的构效关系，以及“类药性”的标准。设计了新型有前途的多功能 ARIs/AOs 假定结构。

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