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

Zhili Xin; Gang Liu; Cele Abad-Zapatero; Zhonghua Pei; Bruce G Szczepankiewicz; Xiaofeng Li; Tianyuan Zhang; Charles W Hutchins; Philip J Hajduk; Stephen J Ballaron; Michael A Stashko; Thomas H Lubben; James M Trevillyan; Michael R Jirousek

doi:10.1016/j.bmcl.2003.08.064

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

Bioorg Med Chem Lett. 2003 Nov 17;13(22):3947-50. doi: 10.1016/j.bmcl.2003.08.064.

Authors

Zhili Xin¹, Gang Liu, Cele Abad-Zapatero, Zhonghua Pei, Bruce G Szczepankiewicz, Xiaofeng Li, Tianyuan Zhang, Charles W Hutchins, Philip J Hajduk, Stephen J Ballaron, Michael A Stashko, Thomas H Lubben, James M Trevillyan, Michael R Jirousek

Affiliation

¹ Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. zhili.xin@abbott.com

PMID: 14592481
DOI: 10.1016/j.bmcl.2003.08.064

Abstract

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.

MeSH terms

Catalytic Domain
Cell Membrane Permeability
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Protein Conformation
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases / antagonists & inhibitors*
Protein Tyrosine Phosphatases / chemistry*
Sensitivity and Specificity
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases