Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications |
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Authors: | Michael C Van Zandt Brian Doan Diane R Sawicki Janet Sredy Alberto D Podjarny |
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Institution: | 1. The Institute for Diabetes Discovery, LLC, 23 Business Park Drive, Branford, CT 06405, USA;2. Département de Biologie Structurale et Génomique, IGBMC, CNRS, INSERM, UDS, 1 rue Laurent Fries, BP 10142, 67404 Illkirch CEDEX, France |
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Abstract: | Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo2,3-b]pyridin-1-yl]acetic acid aldose reductase inhibitors. The lead candidate, 6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo2,3-b]pyridin-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50 > 100 μM), a related enzyme involved in the detoxification of reactive aldehydes. |
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