Iclepertin is a selective glycine transporter 1 (GlyT1) inhibitor that functions by inhibiting GlyT1, thereby modulating intracellular glycine concentration[1-2]. Iclepertin is used in research related to cognitive impairment associated with schizophrenia (CIAS) and Alzheimer's disease[3-4].
In vivo, in a schizophrenia-associated mouse model using C57BL/6JRj mice, Iclepertin (0.3, 1, or 4mg/kg; subcutaneous injection) administered 15 minutes before MK-801 treatment. Iclepertin significantly reversed MK-801-induced deficits in auditory event-related potential N1 amplitude and N1 gating, as well as reductions in 40Hz auditory steady-state response power and intertrial coherence, while also suppressing abnormal basal gamma power elevation. In CD-1 mice treated with MK-801, Iclepertin (0.5, 1.5, or 4.5mg/kg; oral administration) given 60 minutes before behavioral testing. Iclepertin significantly improved working memory deficits and increased spontaneous alternation accuracy. In untreated Wistar rats performing a social recognition task, a single dose of Iclepertin (0.2, 0.6, or 1.8mg/kg; oral administration) administered 60 minutes before training and testing. Iclepertin significantly reduced social investigation time after a 24-hour delay and enhanced social recognition memory performance[5]. Iclepertin (0.2, 0.6, or 2mg/kg; oral administration) administered as a single dose to Wistar rats. Iclepertin resulted in a dose-dependent increase in cerebrospinal fluid glycine levels when measured 90 minutes post-administration[6].
References:
[1] Li N, Wei Y, Li R, et al. Modulation of the human GlyT1 by clinical drugs and cholesterol. Nat Commun. 2025 Mar 11;16(1):2412.
[2] Keefe RSE, Harvey PD, Correll CU, et al. Efficacy and safety of iclepertin for cognitive impairment associated with schizophrenia (CONNEX programme): results from three phase 3 randomised controlled trials. Lancet Psychiatry. 2025 Dec;12(12):906-920.
[3] Rosenbrock H, Desch M, Wunderlich G. Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2023 Oct;273(7):1557-1566.
[4] Ye N, Wang Q, Li Y, et al. Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities. Med Res Rev. 2025 Mar;45(2):755-787.
[5] Rosenbrock H, Dorner-Ciossek C, Giovannini R, et al. Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia. J Pharmacol Exp Ther. 2022 Aug;382(2):223-232.
[6] Rosenbrock H, Desch M, Kleiner O, et al. Evaluation of Pharmacokinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies. Clin Transl Sci. 2018 Nov;11(6):616-623.