Abstract
Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.
MeSH terms
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Animals
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Enzyme Activation
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Female
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Glucokinase / metabolism*
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Hypoglycemic Agents / adverse effects
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology*
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Male
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / enzymology
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Rats
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Rats, Sprague-Dawley
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
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Sulfones / adverse effects
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Sulfones / chemistry*
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Sulfones / pharmacokinetics
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Sulfones / pharmacology*
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Thiazoles / adverse effects
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Thiazoles / chemistry*
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology*
Substances
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2-(4-cyclopropanesulfonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide
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Hypoglycemic Agents
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Sulfones
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Thiazoles
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Glucokinase