Identification of a monoacid-Based, cell permeable, selective inhibitor of protein tyrosine phosphatase 1B

Monoacid-based PTP1B inhibitors with improved physiochemical properties have been investigated. A (2-hydroxy-phenoxy) acetic acid-based phosphotyrosyl mimetic has been linked with an optimized second arylphosphate binding site ligand to produce compound 20 with low micromolar potency against PTP1B,...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2003-11, Vol.13 (22), p.3947-3950
Hauptverfasser:	Xin, Zhili, Liu, Gang, Abad-Zapatero, Cele, Pei, Zhonghua, Szczepankiewicz, Bruce G., Li, Xiaofeng, Zhang, Tianyuan, Hutchins, Charles W., Hajduk, Philip J., Ballaron, Stephen J., Stashko, Michael A., Lubben, Thomas H., Trevillyan, James M., Jirousek, Michael R.
Format:	Artikel
Sprache:	eng
Schlagworte:	Biological and medical sciences Catalytic Domain Cell Membrane Permeability Crystallography, X-Ray Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General and cellular metabolism. Vitamins Medical sciences Pharmacology. Drug treatments Protein Conformation Protein Tyrosine Phosphatase, Non-Receptor Type 1 Protein Tyrosine Phosphatases - antagonists & inhibitors Protein Tyrosine Phosphatases - chemistry Sensitivity and Specificity Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	Monoacid-based PTP1B inhibitors with improved physiochemical properties have been investigated. A (2-hydroxy-phenoxy) acetic acid-based phosphotyrosyl mimetic has been linked with an optimized second arylphosphate binding site ligand to produce compound 20 with low micromolar potency against PTP1B, good selectivity over TCPTP (20-fold) and high cell permeability in the Caco-2 system. The discovery of monoacid-based, cell permeable PTP1B inhibitor 20 with selectivity over TCPTP is reported.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2003.08.064