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Published on: February 7, 2019
Sorbitol dehydrogenase inhibitors (SDIs): a new potent, enantiomeric SDI,
B L Mylari1, P J Oates, D A Beebe
1Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research & Development, Pfizer Inc., Groton, Connecticut 06340, USA. lmylari@home.com
Abstract:
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.
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