Acid Derivatives of Pyrazolo[1,5-a]pyrimidine: The First Class of Aldose Reductase Differential Inhibitors (ARDIs)

Abstract

Aldose reductase, 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, aldose reductase is a Janus-faced enzyme which, besides ruling the polyol pathway, takes part to the antioxidant defence mechanism of the body. In this work we report the evidence that a novel class of compounds, characterized by a pyrazolo[1,5-a]pyrimidine core and a ionisable fragment, is able to modulate differently the catalytic activity of the enzyme, depending on the presence of specific substrates like sugar, toxic aldehydes and glutathione conjugates of toxic aldehydes. These compounds stand out as the first example of aldose reductase differential inhibitors (ARDIs), intended to target long term diabetic complications while leaving unaltered the detoxifying role of the enzyme.