Abstract
In an effort to develop novel small molecule PTP1B inhibitors, a series of bromophenol derivatives were designed, synthesized and evaluated in vitro and in vivo. All of the synthesized compounds displayed weak to potent PTP1B inhibitory activities (5.62-96.25%) at 20 μg/mL. Among these compounds, 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol (9) exhibited enhanced PTP1B inhibitory activity (IC50 = 1.50 μM) than the lead compound BDDPM (IC50 = 2.42 μM) and high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Results of anti-diabetic assay using C57BL/KsJ-db/db mouse model demonstrated that compound 9 was effective at lowering blood glucose, total cholesterol and HbA1c (P < 0.01).
Copyright © 2013 Elsevier Masson SAS. 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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Benzhydryl Compounds / chemical synthesis
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Benzhydryl Compounds / chemistry
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Benzhydryl Compounds / pharmacology*
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Catechols / chemical synthesis
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Catechols / chemistry
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Catechols / pharmacology*
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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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Dose-Response Relationship, Drug
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Drug Discovery*
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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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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Obese
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Molecular Structure
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol
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Benzhydryl Compounds
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Catechols
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Enzyme Inhibitors
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Hypoglycemic Agents
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Recombinant Proteins
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1