Synthesis and biological evaluation of (±)-3-(2-(2-fluorobenzyloxy) naphthalen-6-yl)-2-aminopropanoic acid derivatives as novel PTP1B inhibitors

A series of novel nonphosphonate-based pTyr mimetics comprised (±)-3-(2-(2-fluorobenzyloxy)naphthalen-6-yl)-2-aminopropanoic acid derivatives were identified as reversible and competitive PTP1B inhibitors via a structure-based design approach. Among the compounds studied, 12h was found to have the best in vitro inhibition activity against PTP1B (IC50 = 1.25 ± 0.24 μM) and the best selectivity (3-fold) between PTP1B and TCPTP. These results should provide suitable druglike lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Graphical abstractStructure-based design led to the discovery of novel nonphosphonate-based pTyr mimetics comprised (±)-3-(2-(2-fluorobenzyloxy)naphthalen-6-yl)-2-aminopropanoic acid derivatives (12a–r) as inhibitors of protein tyrosine phosphatase 1B (PTP1B).Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Structure-based design led to the discovery of novel nonphosphonate-based pTyr mimetics. ► These derivatives are potent, competitive, and reversible inhibitors of PTP1B. ► These results should provide suitable druglike lead compounds.