Sorbitol dehydrogenase inhibitors (SDIs):: A new potent, enantiomeric SDI, 4-[2-1R-hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic acid dimethylamide

被引：23
|
作者：
Mylari, BL [1 ]
Oates, PJ [1 ]
Beebe, DA [1 ]
Brackett, NS [1 ]
Coutcher, JB [1 ]
Dina, MS [1 ]
Zembrowski, WJ [1 ]
机构：
[1] Pfizer Inc, Pfizer Global Res & Dev, Dept Cardiovasc & Metab Dis, Groton, CT 06340 USA
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2001年 / 44卷 / 17期
关键词：
D O I：
10.1021/jm0102001
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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 10x 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.
引用
收藏
页码：2695 / 2700
页数：6
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