Potent, selective inhibitors of protein tyrosine phosphatase 1B.
We have previously reported a novel series of oxalyl-aryl-amino benzoic acid-based, catalytic site-directed, competitive, reversible protein tyrosine phosphatase 1B (PTP1B) inhibitors. With readily access to key intermediates, we utilized a solution phase parallel synthesis approach and rapidly identified a highly potent PTP1B inhibitor (19, K(i)=76 nM) with moderate selectivity (5-fold) over T-cell PTPase (TCPTP) through interacting with a second phosphotyrosine binding site (site 2) in the close proximity to the catalytic site.
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA.
Zhili
Z
Xin
Thorsten K
TK
Oost
Cele
C
Abad-Zapatero
Philip J
PJ
Hajduk
Zhonghua
Z
Pei
Bruce G
BG
Szczepankiewicz
Charles W
CW
Hutchins
Steve J
SJ
Ballaron
Mike A
MA
Stashko
Tom
T
Lubben
James M
JM
Trevillyan
Mike R
MR
Jirousek
Gang
G
Liu
D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D019000:Phosphotyrosine / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000201:enzymology
D000577:Amides; D001565:Benzoates; D004791:Enzyme Inhibitors; D008024:Ligands; D019000:Phosphotyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases