Discovery and Structure−Activity Relationship of Oxalylarylaminobenzoic Acids as Inhibitors of Protein Tyrosine Phosphatase 1B
Year: 2003
Type: article
Abstract: Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice.
Source: Journal of Medicinal Chemistry
DOI: 10.1021/jm0205696
Authors: Gang Liu, Bruce G. Szczepankiewicz, Zhonghua Pei, David A. Janowick, Zhili Xin, Philip J. Hajduk, Cele Abad-Zapatero, Heng Liang, Charles W. Hutchins, Stephen W. Fesik, Steve J. Ballaron, Mike A. Stashko, Tom Lubben, Amanda K. Mika, Bradley A. Zinker, James M. Trevillyan, Michael R. Jirousek
Institution: Abbott (United States)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2127622220