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.
Subject(s)
4-Aminobenzoic Acid/chemical synthesis , Aminobenzoates/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Phenylalanine/chemical synthesis , Protein Tyrosine Phosphatases/antagonists & inhibitors , para-Aminobenzoates , 4-Aminobenzoic Acid/pharmacokinetics , 4-Aminobenzoic Acid/pharmacology , Administration, Oral , Amino Acid Sequence , Aminobenzoates/pharmacokinetics , Aminobenzoates/pharmacology , Animals , Biological Availability , Blood Glucose/analysis , Caco-2 Cells , Catalytic Domain , Crystallography, X-Ray , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Magnetic Resonance Spectroscopy , Male , Mice , Models, Molecular , Molecular Sequence Data , Permeability , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacokinetics , Phenylalanine/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/chemistry , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
