Therapeutic intervention with aldose reductase inhibitors appears to be promising for major pathological conditions (i.e., long-term diabetic complications and inflammatory pathologies). So far, however, clinical candidates have failed due to adverse side-effects (spiroimides) or poor bioavailability (carboxylic acids). In this work, we succeeded in the bioisosteric replacement of an acetic acid moiety with that of 1-hydroxypyrazole. This new scaffold appears to have a superior physicochemical profile, while attaining inhibitory activity in the submicromolar range.
Keywords: 1,4-dihydroxynonene; 4-hydroxynonenal; AGEs; ALR1; ALR2; ARI; Aldose reductase inhibitors; BEI; Bioisosterism; DHN; GSH; HNE; Inflammatory pathologies; LE; LELP; LLE; Long-term diabetic complications; Molecular obesity; ROS; SDH; advanced glycation end-products; aldehyde reductase; aldose reductase; aldose reductase inhibitor; binding efficiency index; glutathione; ligand efficiency; ligand efficiency-dependent lipophilicity; lipophilic ligand efficiency; reactive oxygen species; sorbitol dehydrogenase.
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