Abstract
The glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.
MeSH terms
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Aminopyridines / chemistry
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Aminopyridines / pharmacology*
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Animals
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / metabolism
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Crystallography, X-Ray
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Glucokinase / antagonists & inhibitors*
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Glucokinase / metabolism
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Glucose / metabolism
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology*
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Liver / cytology
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Liver / drug effects*
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Liver / metabolism
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Rats
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Rats, Sprague-Dawley
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Sulfones / chemistry*
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Sulfones / pharmacology
Substances
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2-(4-(5-((6-aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-chlorophenyl)propane-1,2-diol
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Aminopyridines
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Carrier Proteins
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Hypoglycemic Agents
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Small Molecule Libraries
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Sulfones
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glucokinase regulatory protein
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Glucokinase
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Glucose
Associated data
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PDB/4OP1
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PDB/4OP2
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PDB/4OP3