4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B.
Bioorg Med Chem
; 22(14): 3670-83, 2014 Jul 15.
Article
in En
| MEDLINE
| ID: mdl-24906513
ABSTRACT
Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2-10 fold selectivity over a panel of PTP's. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carboxylic Acids
/
Cell Membrane Permeability
/
4-Quinolones
/
Enzyme Inhibitors
/
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2014
Type:
Article
Affiliation country:
China