Glycine transporters (GlyTs) are plasmalemmal neurotransmitter transporters. GlyTs, which regulate brain glycine levels, is an inhibitory neurotransmitter with co-agonist activity for NMDA receptors (NMDARs). Meanwhile, GlyTs comprise glycine transporter type 1 (SLC6A9; GlyT1) and glycine transporter type 2 (SLC6A5; Glyt2). For instance, GlyT1 is a transporter that functions to regulate the synaptic levels of glycine. Moreover, GlyT1 is involved in glutamatergic neurotransmission, and is an important target for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia and Alzheimer disease.

BI-425809 is a potent, selective and orally active glycine transporter 1 (GlyT1) inhibitor. However, BI-425809 is inactive against GlyT2. Generally, this compound has the potential to study cognitive impairment in Alzheimer disease and schizophrenia. In addition, BI-425809 inhibits GlyT1 with the IC50 values of 5.2 nM in rat primary neurons and 5.0 nM in human SK-N-MC cells. A translational study evaluated the effects of BI-425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Certainly, the results suggest that BI-425809 has a favorable pharmacokinetic profile. In rats, a single oral administration of BI-425809 resulted in a dose-dependent increase in glycine CSF levels. Consequently, This shows that glycine levels in CSF can be used to assess GlyT1 inhibition centrally, thereby supporting the use of CSF glycine analysis for confirming central target engagement in humans.

To sum up, BI-425809 is a selective and orally active GlyT1 inhibitor, which could provide an effective study for cognitive impairment associated with schizophrenia.


[1] Holger Rosenbrock, et al. Clin Transl Sci. 2018 Nov;11(6):616-623.

[2] W Wolfgang Fleischhacker, et al. Lancet Psychiatry. 2021 Mar;8(3):191-201.