Abstract
Fifteen novel sulfathiazole-related compounds were designed as PTP1B inhibitors based on a previously reported allosteric inhibitor (1) of PTP1B. These compounds were synthesized and evaluated against human recombinant PTP1B. Six compounds (3, 4, 8 and 14-16) exhibited significant inhibitory activity against PTP1B. The most active compound (16) showed IC50 value of 3.2 μM and kinetic analysis indicated that it is a non-competitive inhibitor of PTP1B. Furthermore, compound 16 demonstrated excellent selectivity to PTP1B over other PTPs. It also displayed in vivo insulin sensitizing effect in the insulin resistant mice.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Disease Models, Animal
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Insulin / metabolism
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Insulin Resistance
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Mice
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Models, Molecular
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Molecular Conformation
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
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Sulfathiazoles / chemical synthesis
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Sulfathiazoles / chemistry*
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Sulfathiazoles / pharmacology*
Substances
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Enzyme Inhibitors
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Insulin
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Recombinant Proteins
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Sulfathiazoles
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1