Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B.

Liu G, Szczepankiewicz BG, Pei Z, Janowick DA, Xin Z, Hajduk PJ, Abad-Zapatero C, Liang H, Hutchins CW, Fesik SW, Ballaron SJ, Stashko MA, Lubben T, Mika AK, Zinker BA, Trevillyan JM, Jirousek MR
J Med Chem. 2003 46 (11): 2093-103

PMID: 12747781 · DOI:10.1021/jm0205696

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.

MeSH Terms (26)

4-Aminobenzoic Acid Administration, Oral Amino Acid Sequence Aminobenzoates Animals Biological Availability Blood Glucose Caco-2 Cells Catalytic Domain Crystallography, X-Ray Enzyme Inhibitors Humans Hypoglycemic Agents Magnetic Resonance Spectroscopy Male Mice Models, Molecular Molecular Sequence Data para-Aminobenzoates Permeability Phenylalanine Protein Tyrosine Phosphatase, Non-Receptor Type 1 Protein Tyrosine Phosphatases Rats Stereoisomerism Structure-Activity Relationship

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