Abstract
Inhibition of AMP deaminase (AMPD) holds the potential to elevate intracellular adenosine and AMP levels and, therefore, to augment adenosine signaling and activation of AMP-activated protein kinase (AMPK). To test the latter hypothesis, novel AMPD pan inhibitors were synthesized and explored using a panel of in vitro, ex vivo, and in vivo models focusing on confirming AMPD inhibitory potency and the potential of AMPD inhibition to improve glucose control in vivo. Repeated dosing of selected inhibitors did not improve glucose control in insulin-resistant or diabetic rodent disease models. Mice with genetic deletion of the muscle-specific isoform Ampd1 did not showany favorable metabolic phenotype despite being challenged with high-fat diet feeding. Therefore, these results do not support the development of AMPD inhibitors for the treatment of type 2 diabetes.
MeSH terms
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AMP Deaminase / antagonists & inhibitors*
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AMP Deaminase / genetics
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AMP Deaminase / metabolism
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Animals
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Blood Glucose / analysis
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Cells, Cultured
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Diabetes Mellitus, Experimental / drug therapy
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Diabetes Mellitus, Experimental / enzymology*
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / pathology
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Diet, High-Fat
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Disease Models, Animal
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Female
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Hepatocytes / enzymology
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Insulin / blood
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Insulin Resistance
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Obese
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Obesity / drug therapy
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Obesity / enzymology*
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Obesity / metabolism
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Obesity / pathology
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Protein Binding
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology
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Small Molecule Libraries / therapeutic use
Substances
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Blood Glucose
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Enzyme Inhibitors
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Insulin
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Recombinant Proteins
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Small Molecule Libraries
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AMP Deaminase
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AMPD1 protein, mouse