Discovery of novel and potent heterocyclic carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors

A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure–activity relationship (SAR) optimization resulted in identification of several potent, selective (over the highly homologous T-cell protein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very good oral (% F = 13–70) bio-availability.

Graphical abstractA series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail are described. Structure–activity relationship (SAR) optimization resulted in identification of potent, selective and orally bio-available PTP1B inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide