Abstract
Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Binding Sites
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Crystallography, X-Ray
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Diabetes Mellitus, Type 2 / drug therapy
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Diabetes Mellitus, Type 2 / etiology
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Half-Life
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Humans
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Insulin Resistance
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Kinetics
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Molecular Dynamics Simulation
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Obesity / complications
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Obesity / pathology
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Phosphorylation / drug effects
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Protein Tyrosine Phosphatases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Purines / chemistry*
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Purines / metabolism
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Purines / pharmacology
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Purines / therapeutic use
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Signal Transduction / drug effects
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Purines
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Proto-Oncogene Proteins c-akt
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Protein Tyrosine Phosphatases