FP802 dihydrochloride is an orally active potent TwinF interface inhibitor that disrupts and detoxifies the NMDAR/TRPM4 death complex. FP802 dihydrochloride exerts powerful neuroprotective effects in the 5xFAD mouse model of Alzheimer’s disease (AD) by preventing cognitive decline, preserving neuronal structural integrity, reducing amyloid-β plaque formation, and mitigating mitochondrial pathology [1]. FP802 dihydrochloride stops loss of motor neurons, reduces serum neurofilament light chain (NfL) levels, improves motor performance, and extends life in a mouse model of amyotrophic lateral sclerosis (ALS) [2]. FP802 dihydrochloride can be used for AD and ALS research [1] [2].
In Vivo, FP802 (10 and 40 mg/kg, p.o., daily for 4 months) dihydrochloride rescues cognitive function, prevents neuronal structure degeneration, and reduces amyloid pathology in 5xFAD mice[1]. FP802 (40 mg/kg, s.c., daily from ~week 15 for 4 weeks) dihydrochloride safely halts motor neuron degeneration and extends survival in ALS mice by targeting the NMDAR/TRPM4 complex[2].
In Vitro, FP802 (8 μM, 24-72 h) hydrochloride disrupts the NMDAR/TRPM4 complex and provides neuroprotection in cellular models, without directly affecting neurite outgrowth[1]. FP802 (10 μM, 30 min) hydrochloride exhibits potent neuroprotection against glutamate (20 μM)-mediated toxicity (IC50 = 8.7 µM) and restores NMDA-suppressed immediate-early gene expression to physiological levels[2]. FP802 hydrochloride shows no antagonistic activity against NMDARs in HEK293 cells (IC50 > 250 μM for both, GluN1/GluN2A and GluN1/GluN2B)[2]. FP802 (30 min) hydrochloride dose-dependently blocks NMDA-induced death of post-mitotic neurons in forebrain organoids derived from sporadic ALS patient induced pluripotent stem cells (iPSCs)[2].
References:
[1]. Yan J, et al. The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease. Mol Psychiatry. 2025 Aug 26.
[2]. Yan J, et al. TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS. Cell Rep Med. 2024 Feb 20;5(2):101413.
In Vivo, FP802 (10 and 40 mg/kg, p.o., daily for 4 months) dihydrochloride rescues cognitive function, prevents neuronal structure degeneration, and reduces amyloid pathology in 5xFAD mice[1]. FP802 (40 mg/kg, s.c., daily from ~week 15 for 4 weeks) dihydrochloride safely halts motor neuron degeneration and extends survival in ALS mice by targeting the NMDAR/TRPM4 complex[2].
In Vitro, FP802 (8 μM, 24-72 h) hydrochloride disrupts the NMDAR/TRPM4 complex and provides neuroprotection in cellular models, without directly affecting neurite outgrowth[1]. FP802 (10 μM, 30 min) hydrochloride exhibits potent neuroprotection against glutamate (20 μM)-mediated toxicity (IC50 = 8.7 µM) and restores NMDA-suppressed immediate-early gene expression to physiological levels[2]. FP802 hydrochloride shows no antagonistic activity against NMDARs in HEK293 cells (IC50 > 250 μM for both, GluN1/GluN2A and GluN1/GluN2B)[2]. FP802 (30 min) hydrochloride dose-dependently blocks NMDA-induced death of post-mitotic neurons in forebrain organoids derived from sporadic ALS patient induced pluripotent stem cells (iPSCs)[2].
References:
[1]. Yan J, et al. The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease. Mol Psychiatry. 2025 Aug 26.
[2]. Yan J, et al. TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS. Cell Rep Med. 2024 Feb 20;5(2):101413.