Discovery of 4-(Arylethynyl)piperidine Derivatives as Potent Nonsaccharide O -GlcNAcase Inhibitors for the Treatment of Alzheimer's Disease.

Inhibiting O -GlcNAcase and thereby up-regulation of the O -GlcNAc levels of tau was a potential approach for discovering AD treatments. Herein, a series of novel highly potent OGA inhibitors embracing a 4-(arylethynyl)piperidine moiety was achieved by capitalizing on the substrate recognition domain. Extensive structure-activity relationships resulted in compound 81 with significant enzymatic inhibition (IC 50 = 4.93 ± 2.05 nM) and cellular potency (EC 50 = 7.47 ± 3.96 nM in PC12 cells). It markedly increased the protein O -GlcNAcylation levels and reduced the phosphorylation on Ser199, Thr205, and Ser396 of tau in the OA-injured SH-SY5Y cell model, suggesting its potential role for AD treatment. In fact, an in vivo efficacy of ameliorating cognitive impairment was observed following treatment of APP/PS1 mice with compound 81 (100 mg/kg). Additionally, the appropriate plasma PK and beneficial BBB penetration properties were also observed. Compound 81 deserves to be further explored as an anti-AD agent.