Identification of new non-carboxylic acid containing inhibitors of aldose reductase

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 11; pp. 4049 - 4055
• Main Authors: Maccari, Rosanna, Ciurleo, Rosella, Giglio, Marco, Cappiello, Mario, Moschini, Roberta, Corso, Antonella Del, Mura, Umberto, Ottanà, Rosaria
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2010; Elsevier
• Subjects: 2,4-Thiazolidinediones; Aldehyde Reductase - antagonists & inhibitors; Aldose reductase inhibitors; Animals; Biological and medical sciences; Chlorofluorocarbons, Methane; Diabetes complications; Enzyme Inhibitors - chemistry; General and cellular metabolism. Vitamins; Humans; In vitro inhibition; Ketones - chemical synthesis; Ketones - pharmacology; Medical sciences; Pharmacology. Drug treatments; Structure-Activity Relationship; Thiazolidinediones; Aldose reductase inhibitors; 2,4-Thiazolidinediones; Diabetes complications; In vitro inhibition; Endocrinopathy; Enzyme; Diabetes mellitus; Enzyme inhibitor; Thiazolidinedione derivatives; Haloketone; In vitro; Biological activity; Aldehyde reductase; Complication; Oxidoreductases; Fluorine Organic compounds; Inhibition; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.016

New non-carboxylic acid containing 5-arylidene-2,4-thiazolidinedione derivatives have been identified as aldose reductase inhibitors active at low micromolar doses. Non-carboxylic acid containing bioisosteres of (5-arylidene-2,4-dioxothiazolidin-3-yl)acetic acids, which are active as aldose reductase (ALR2) inhibitors, were designed by replacing the carboxylic group with the trifluoromethyl ketone moiety. The in vitro evaluation of the ALR2 inhibitory effects of these trifluoromethyl substituted derivatives led to the identification of two inhibitors effective at low micromolar doses. It was further confirmed that a carboxylic chain on N-3 of the thiazolidinedione scaffold is a determining requisite to obtain the highest efficacy levels; however, it is not essential for the interaction with the target enzyme and it can be replaced by different polar groups, thus obtaining less ionised or unionised inhibitors.