Aldose reductase (AKR1B1), the key enzyme of the polyol pathway, plays a crucial role in the development of long-term complications affecting diabetic patients. Nevertheless, the expedience of inhibiting this enzyme to treat diabetic complications has failed, due to the emergence of side effects from compounds under development. Actually AKR1B1 is a Janus-faced enzyme which, besides ruling the polyol pathway, takes part in the antioxidant defense mechanism of the body. In this work we report the evidence that a class of compounds, characterized by a pyrazolo[1,5-a]pyrimidine core and an ionizable fragment, modulates differently the catalytic activity of the enzyme, depending on the presence of specific substrates such as sugar, toxic aldehydes, and glutathione conjugates of toxic aldehydes. The study stands out as a systematic attempt to generate aldose reductase differential inhibitors (ARDIs) intended to target long-term diabetic complications while leaving unaltered the detoxifying role of the enzyme.

中文翻译：

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吡唑并[1,5-a]嘧啶的酸衍生物作为醛糖还原酶差异抑制剂

醛糖还原酶（AKR1B1）是多元醇途径的关键酶，在影响糖尿病患者的长期并发症的发生中起着至关重要的作用。然而，由于正在开发的化合物的副作用的出现，抑制这种酶治疗糖尿病并发症的方法失败了。实际上，AKR1B1是一种面对Janus的酶，除了决定多元醇途径外，还参与人体的抗氧化防御机制。在这项工作中，我们报告的证据表明，以吡唑并[1,5-a]嘧啶核和可电离片段为特征的一类化合物根据特定底物（例如糖）的存在而不同地调节酶的催化活性。 ，有毒醛和有毒醛的谷胱甘肽共轭物。