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, good selectivity over TCPTP (20-fold) and high cell permeability in the Caco-2 system.
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. zhili.xin@abbott.com
Zhili
Z
Xin
Gang
G
Liu
Cele
C
Abad-Zapatero
Zhonghua
Z
Pei
Bruce G
BG
Szczepankiewicz
Xiaofeng
X
Li
Tianyuan
T
Zhang
Charles W
CW
Hutchins
Philip J
PJ
Hajduk
Stephen J
SJ
Ballaron
Michael A
MA
Stashko
Thomas H
TH
Lubben
James M
JM
Trevillyan
Michael R
MR
Jirousek
D020134:Catalytic Domain; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases