title: Synthesis and biological activity of a novel class of pyridazine analogues as non-competitive reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B).
abstract: 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 12 mp showed 20-fold selectivity for PTP1B (IC50=5.6 microM) versus both TCPTP and LAR (>100 microM, 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.
authors.affiliation: Biovitrum AB, Department of Medicinal Chemistry and Biology, Uppsala, Sweden. charlotta.liljebris@biovitrum.com
authors.forename: Charlotta
authors.initials: C
authors.lastname: Liljebris
authors.forename: Jessica
authors.initials: J
authors.lastname: Martinsson
authors.forename: Lars
authors.initials: L
authors.lastname: Tedenborg
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
authors.forename: Emma
authors.initials: E
authors.lastname: Barker
authors.forename: James E S
authors.initials: JE
authors.lastname: Duffy
authors.forename: Alf
authors.initials: A
authors.lastname: Nygren
authors.forename: Stephen
authors.initials: S
authors.lastname: James
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002463:Cell Membrane Permeability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D007700:Kinetics; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D011724:Pyridazines; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516610:Ptpn1 protein, rat