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

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

doi:10.1021/jm0205696

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

J Med Chem. 2003 May 22;46(11):2093-103. doi: 10.1021/jm0205696.

Authors

Gang Liu¹, 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

Affiliation

¹ Metabolic Disease Research and Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. gang.liu@abbott.com

PMID: 12747781
DOI: 10.1021/jm0205696

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.

MeSH terms

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

Substances

Aminobenzoates
Blood Glucose
Enzyme Inhibitors
Hypoglycemic Agents
N-acetyl-4-((carboxycarbonyl)(2-carboxyphenyl)amino)-N-pentyl-3-(2-hydroxyethane)phenylalaninamide
para-Aminobenzoates
Phenylalanine
PTPN1 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases
Ptpn1 protein, mouse
Ptpn1 protein, rat
4-Aminobenzoic Acid