1. Design and synthesis of highly potent and selective (2-arylcarbamoyl-phenoxy)-acetic acid inhibitors of aldose reductase for treatment of chronic diabetic complications
- Author
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Alberto Podjarny, Andre Mitschler, Kerry Combs, Evelyn O. Sibley, Al Sabetta, Erin E. McCann, Anne L. Carrington, Eduardo Howard, Diane R. Sawicki, Janet Sredy, Brenda R. Flam, and Michael C. Van Zandt
- Subjects
Male ,Tolrestat ,Stereochemistry ,Carboxylic acid ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Aldehyde Reductase ,Drug Discovery ,Animals ,Sorbitol ,Enzyme Inhibitors ,Molecular Biology ,Acetic Acid ,chemistry.chemical_classification ,Aldose reductase ,biology ,Organic Chemistry ,Rats ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,Chronic Disease ,biology.protein ,Molecular Medicine ,Pharmacophore - Abstract
Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective (2-arylcarbamoyl-phenoxy)-acetic acid aldose reductase inhibitors. The compound class features a core template that utilizes an intramolecular hydrogen bond to position the key structural elements of the pharmacophore in a conformation, which promotes a high binding affinity. The lead candidate, example 40 , 5-fluoro-2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-phenoxyacetic acid, inhibits aldose reductase with an IC 50 of 30 nM, while being 1100 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. In addition, example 40 lowers nerve sorbitol levels with an ED 50 of 31 mg/kg/d po in the 4-day STZ-induced diabetic rat model.
- Published
- 2004
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