Isoxazole carboxylic acids as protein tyrosine phosphatase 1B (PTP1B) inhibitors.
Guided by X-ray crystallography, we have extended the structure-activity relationship (SAR) study on an isoxazole carboxylic acid-based PTP1B inhibitor (1) and more potent and equally selective (>20-fold selectivity over the highly homologous T-cell PTPase, TCPTP) PTP1B inhibitors were identified. Inhibitor 7 demonstrated good cellular activity against PTP1B in COS 7 cells.
Zhao
Hongyu
H
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. hongyu.zhao@abbott.com
Liu
Gang
G
Xin
Zhili
Z
Serby
Michael D
MD
Pei
Zhonghua
Z
Szczepankiewicz
Bruce G
BG
Hajduk
Philip J
PJ
Abad-Zapatero
Cele
C
Hutchins
Charles W
CW
Lubben
Thomas H
TH
Ballaron
Stephen J
SJ
Haasch
Deanna L
DL
Kaszubska
Wiweka
W
Rondinone
Cristina M
CM
Trevillyan
James M
JM
Jirousek
Michael R
MR
D000818:Animals; D019556:COS Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D007555:Isoxazoles; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases