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.
MeSH terms
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Administration, Oral
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Animals
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Diabetes Mellitus, Experimental / metabolism
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Fructose / antagonists & inhibitors
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Fructose / biosynthesis
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Humans
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L-Iditol 2-Dehydrogenase / antagonists & inhibitors*
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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Sciatic Nerve / metabolism
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Stereoisomerism
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Tissue Distribution
Substances
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4-(2-hydroxyethylpyrimidin-1-yl)piperazine-1-sulfonic acid dimethylamide
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Enzyme Inhibitors
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Pyrimidines
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Sulfonamides
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Fructose
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L-Iditol 2-Dehydrogenase