Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B.
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.
Metabolic Disease Research and Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. gang.liu@abbott.com
Gang
G
Liu
Bruce G
BG
Szczepankiewicz
Zhonghua
Z
Pei
David A
DA
Janowick
Zhili
Z
Xin
Philip J
PJ
Hajduk
Cele
C
Abad-Zapatero
Heng
H
Liang
Charles W
CW
Hutchins
Stephen W
SW
Fesik
Steve J
SJ
Ballaron
Mike A
MA
Stashko
Tom
T
Lubben
Amanda K
AK
Mika
Bradley A
BA
Zinker
James M
JM
Trevillyan
Michael R
MR
Jirousek
D010129:4-Aminobenzoic Acid / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000595:Amino Acid Sequence; D062365:Aminobenzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000032:analysis; D018938:Caco-2 Cells; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010539:Permeability; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates
D062365:Aminobenzoates; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; C474819:N-acetyl-4-((carboxycarbonyl)(2-carboxyphenyl)amino)-N-pentyl-3-(2-hydroxyethane)phenylalaninamide; D062366:para-Aminobenzoates; D010649:Phenylalanine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; C516610:Ptpn1 protein, rat; D010129:4-Aminobenzoic Acid