Sorbitol Dehydrogenase Inhibitors (SDIs):  A New Potent, Enantiomeric SDI, 4-[2-1R-Hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic Acid Dimethylamide

We report here on our medicinal chemistry and pharmacology efforts to provide a potent sorbitol dehydrogenase inhibitor (SDI) as a tool to probe a recently disclosed hypothesis centered on the role of sorbitol dehydrogenase (SDH) in the second step of the polyol pathway, under conditions of high glu...

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Veröffentlicht in:Journal of medicinal chemistry 2001-08, Vol.44 (17), p.2695-2700
Hauptverfasser: Mylari, Banavara L, Oates, Peter J, Beebe, David A, Brackett, Nathaniel S, Coutcher, James B, Dina, Michael S, Zembrowski, William J
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Sprache:eng
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Zusammenfassung:We report here on our medicinal chemistry and pharmacology efforts to provide a potent sorbitol dehydrogenase inhibitor (SDI) as a tool to probe a recently disclosed hypothesis centered on the role of sorbitol dehydrogenase (SDH) in the second step of the polyol pathway, under conditions of high glucose flux. Starting from a weak literature lead, 2, and through newly developed structure−activity relationships, we have designed and executed an unambiguous synthesis of enantiomeric SDI, 6, which is at least 10× more potent than 2. Also, 6 potently inhibits SDH in streptozotocin-diabetic rat sciatic nerve. We have described an expedient synthesis of a key building template, 33, for future research in the SDI area that may facilitate the discovery of even more potent SDIs with longer duration of action in vivo.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0102001