Design and synthesis of novel benzoic acid derivatives as striatal-enriched protein tyrosine phosphatase (STEP) inhibitors with neuroprotective properties.

As a central nervous system-specific member of the protein tyrosine phosphatase (PTP) family, the striatal-enriched protein tyrosine phosphatase (STEP) is an attractive drug target for neurodegenerative diseases. Here, we reported the discovery of a series of benzoic acid derivatives as new STEP inhibitors. Among them, compound 14b exhibited good STEP inhibitory activity and displayed selectivity against other PTPs. The neuroprotective activity of compound 14b was evaluated against glutamate-induced oxidative cell death in HT22 cells. Results indicated that compound 14b co-treatment prevented cell death and reduced cellular ROS accumulation. Compound 14b inhibited cell apoptosis by upregulating BCL-2 expression and downregulating BAX and C-caspase3 expression. Moreover, compound 14b was also found to provide neuroprotection to primary cortical neurons after oxygen-glucose deprivation/reoxygenation (OGD/R). Further structural elaboration of compound 14b may provide new drug candidates for neurodegenerative diseases.