Synthesis and biological activity of a novel class of pyridazine analogues as non-competitive reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B)
| Autor: | Stephen James, Lars Tedenborg, Jessica Martinsson, Alf Nygren, James Duffy, Charlotta Liljebris, Emma Barker, Meredith Williams |
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| Rok vydání: | 2002 |
| Předmět: |
Cell Membrane Permeability
Stereochemistry Clinical Biochemistry Pharmaceutical Science Protein tyrosine phosphatase Biochemistry Cell Line Pyridazine Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Insulin Enzyme Inhibitors Phosphorylation Molecular Biology Protein Tyrosine Phosphatase Non-Receptor Type 1 chemistry.chemical_classification Binding Sites biology Organic Chemistry Biological activity Receptor Insulin Enzyme assay Rats Pyridazines Kinetics Insulin receptor Enzyme chemistry Enzyme inhibitor biology.protein Molecular Medicine Insulin Resistance Protein Tyrosine Phosphatases Hydrophobic and Hydrophilic Interactions Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry. 10:3197-3212 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/s0968-0896(02)00176-1 |
| Popis: | A series of novel pyridazine analogues were prepared and the structure–activity relationship of their behavior as inhibitors of PTP1B was evaluated. Most of the analogues had potencies in the low micromolar range. The in vitro kinetics of this compound series demonstrated that they were reversible non-competitive binders. This indicates that there may exist another site in the enzyme through which enzyme activity can be inhibited, which is not a recognized interaction domain. Some of the analogues exhibited high selectivity for other PTPases, for example, compound 12mp showed 20-fold selectivity for PTP1B (IC 50 =5.6 μM) versus both TCPTP and LAR (>100 μM, respectively). In contrast to many tyrosine phosphatase mimetic inhibitors, this compound class lacks negative charge and thus showed high permeability across cell membranes. Selective analogues in the series were analyzed in an in vitro cellular assay, which showed increased insulin-stimulated insulin receptor phosphorylation. |
| Databáze: | OpenAIRE |
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