The sulfamic acid phosphotyrosine mimetic was coupled with a previously known malonate template to obtain highly selective and potent inhibitors of HPTPbeta. Potentially hydrolyzable malonate ester functionalities were replaced with 1,2,4-oxadiazoles without a significant effect on HPTPbeta potency.
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Study of triaryl-based sulfamic acid derivatives as HPTPβ inhibitors.
Bioorg Med Chem
December 2020
National Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
A series of novel triaryl-based sulfamic acid analogs was designed, synthesized and evaluated as inhibitors of human protein tyrosine phosphatase beta (HPTPβ). A novel, easy and efficient synthetic method was developed for target compounds, and the activity determination results showed that most of compounds were good HPTPβ inhibitors. Interestingly, the compounds G4 and G25 with simple structure not only showed potent inhibitory activity on HPTPβ but also had good inhibitory selectivity over other PTPs (PTP1B, SHP2, LAR and TC-PTP).
View Article and Find Full Text PDFSynthesis and biological evaluation of (3'-amino-[1,1'-biphenyl]-4-yl) sulfamic acid derivatives as novel HPTPβ inhibitors.
Bioorg Chem
December 2018
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address:
A series of novel (3'-amino-[1,1'-biphenyl]-4-yl) sulfamic acid derivatives were designed as nonphosphonate-based phosphotyrosy (pTyr) mimetics, synthesized and screened for use as HPTPβ inhibitors. Compounds C22 and C2 showed favorable HPTPβ inhibitory activity and better selectivity for HPTPβ than for PTP1B and SHP2. Docking results suggested that compounds C2 and C22 could not only efficiently fit into the catalytic site of the HPTPβ enzyme but also interact with the Lys1807, Arg1809 and Lys1811 residues of the secondary binding site, which was next to the catalytic center of the enzyme.
View Article and Find Full Text PDFEffects of hPTPβ inhibitor on microcirculation of rat cremaster muscle flap following ischemia-reperfusion injury.
Microsurgery
September 2017
Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH.
Introduction: Inhibition of protein tyrosine phosphatases (PTP) enhances endothelial receptor tyrosine kinases activation and may have beneficial effects on vessel growth and improve blood flow to ischemic tissue. The purpose of this study is to determine influence of hPTPß inhibitors on ischemia-reperfusion injury in muscle flap.
Materials And Methods: Following cremaster muscle dissection, 60 rats divided into 10 experimental groups (placebo and treatment groups following 0, 1, 2, 3, and 4 h of ischemia).
Tyrosine phosphatase beta regulates angiopoietin-Tie2 signaling in human endothelial cells.
Angiogenesis
June 2009
Terrence Donnelly Heart Centre and Division of Cardiology, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada.
Objectives: The endothelial cell (EC)-selective receptor tyrosine kinase, Tie2, and its ligands angiopoietin Ang-1 and Ang-2, are essential for blood vessel maintenance and repair. Ang-1 is an agonist of Tie2 receptor activation, whereas Ang-2 is a context-dependent antagonist/agonist. Therefore, we investigated the role of the EC-selective phosphatase, human protein tyrosine phosphatase beta (HPTPbeta), in regulating Tie2 activity.
View Article and Find Full Text PDFEngineering the catalytic domain of human protein tyrosine phosphatase beta for structure-based drug discovery.
Acta Crystallogr D Biol Crystallogr
December 2006
Structural Biology, Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45140, USA.
Protein tyrosine phosphatases (PTPs) play roles in many biological processes and are considered to be important targets for drug discovery. As inhibitor development has proven challenging, crystal structure-based design will be very helpful to advance inhibitor potency and selectivity. Successful application of protein crystallography to drug discovery heavily relies on high-quality crystal structures of the protein of interest complexed with pharmaceutically interesting ligands.
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