title: 1-Hydroxypyrazole as a bioisostere of the acetic acid moiety in a series of aldose reductase inhibitors.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papastavrou
authors.forename: Maria
authors.initials: M
authors.lastname: Chatzopoulou
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Pegklidou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Nicolaou
mesh_terms: D019342:Acetic Acid / Q000737:chemistry*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D007904:Lens Cortex, Crystalline / Q000201:enzymology; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D000449:Aldehyde Reductase; D019342:Acetic Acid
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