Fosgonimeton is a highly specific small-molecule positive modulator of the HGF/MET(Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition) neurotrophic system. Fosgonimeton is a prodrug optimized for subcutaneous (SC) administration and is rapidly converted into the active metabolite fosgo-AM in plasma. Fosgo-AM crosses the blood-brain barrier and enhances the interaction of HGF with its receptor tyrosine kinase MET, inducing downstream signaling through PI3k/Akt and MAPK pathways and augmenting N-methyl-D-aspartate (NMDA) receptor-mediated long-term potentiation through protein kinase C. Fosgonimeton has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia[1][2].
In vivo, Subcutaneous administration of Fosgonimeton (0.125, 0.25, 0.5, 1, and 2mg/kg) for 14 days significantly restored cognitive function at all tested doses in Aβ peptide-treated adult male Wistar rats[2]. Subcutaneous administration of Fosgonimeton at doses of 0.25, 0.5, and 1.25mg/kg for 14 consecutive days significantly improved cognitive deficits in LPS-treated CD-1 mice[3].
References:
[1] ua X, Church K, Walker W, et al. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial. J Alzheimers Dis. 2022;86(3):1399-1413.
[2] Reda SM, Setti SE, Berthiaume AA, et al. Fosgonimeton attenuates amyloid-beta toxicity in preclinical models of Alzheimer's disease. Neurotherapeutics. 2024;21(4):e00350.
[3] Johnston JL, et al. Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia. Neurotherapeutics. 2023 Mar;20(2):431-451.
Fosgonimeton是一种高度特异性的HGF/MET（肝细胞生长因子/间充质-上皮转化因子受体）神经营养系统的小分子正向调节剂。Fosgonimeton是一种适合皮下给药的前药，可在血浆中迅速转化为活性代谢物fosgo-AM。Fosgo-AM能够穿过血脑屏障，增强肝细胞生长因子（HGF）与其络氨酸激酶受体（MET）的相互作用，通过PI3k/Akt和MAPK通路诱导下游信号传导，并通过蛋白激酶C增强N-methyl-D-aspartate（NMDA）受体介导的长期增强作用，在痴呆症的临床前模型中已显示出神经营养和促进认知的效果[1][2]。
体内实验中，在Aβ肽处理的成年雄性Wistar大鼠中，皮下注射Fosgonimeton（0.125、0.25、0.5、1 和 2mg/kg）连续14天，在所有测试剂量下均显著恢复了大鼠认知功能[2]。连续14天以0.25、0.5和1.25mg/kg剂量对LPS处理的CD-1小鼠进行Fosgonimeton皮下给药，均显著改善了小鼠认知功能缺陷[3]。