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Acetic acid aldose reductase inhibitors bearing a five-membered heterocyclic core with potent topical activity in a visual impairment rat model.

Authors: La Motta, C  Sartini, S  Salerno, S  Simorini, F  Taliani, S  Marini, AM  Da Settimo, F  Marinelli, L  Limongelli, V  Novellino, E 
Citation: La Motta C, etal., J Med Chem. 2008 Jun 12;51(11):3182-93. doi: 10.1021/jm701613h. Epub 2008 May 2.
Pubmed: (View Article at PubMed) PMID:18452283
DOI: Full-text: DOI:10.1021/jm701613h

A number of 1,2,4-oxadiazol-5-yl-acetic acids and oxazol-4-yl-acetic acids were synthesized and tested for their ability to inhibit aldose reductase (ALR2). The oxadiazole derivatives, 7c, 7f, 7i, and 8h, 8i, proved to be the most active compounds, exhibiting inhibitory levels in the submicromolar range. In this series, the phenyl group turned out to be the preferred substitution pattern, as its lengthening to a benzyl moiety determined a general reduction of the inhibitory potency. The lead compound, 2-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]acetic acid, 7c, showed an excellent in vivo activity, proving to prevent cataract development in severely galactosemic rats when administered as an eye-drop solution in the precorneal region of the animals. Computational studies on the ALR2 inhibitors were performed to rationalize the structure-activity relationships observed and to provide the basis for further structure-guided design of novel ALR2 inhibitors.


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RGD Object Information
RGD ID: 8548671
Created: 2014-03-18
Species: All species
Last Modified: 2014-03-18
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.