Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia.
ATH-1017
Alzheimer’s dementia
Fosgonimeton
Hepatocyte growth factor (HGF)
Neurodegeneration
Neurotrophic factor
Journal
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
ISSN: 1878-7479
Titre abrégé: Neurotherapeutics
Pays: United States
ID NLM: 101290381
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
accepted:
23
10
2022
medline:
25
4
2023
pubmed:
21
12
2022
entrez:
20
12
2022
Statut:
ppublish
Résumé
All types of dementia, including Alzheimer's disease, are debilitating neurodegenerative conditions marked by compromised cognitive function for which there are few effective treatments. Positive modulation of hepatocyte growth factor (HGF)/MET, a critical neurotrophic signaling system, may promote neuronal health and function, thereby addressing neurodegeneration in dementia. Here, we evaluate a series of novel small molecules for their ability to (1) positively modulate HGF/MET activity, (2) induce neurotrophic changes and protect against neurotoxic insults in primary neuron culture, (3) promote anti-inflammatory effects in vitro and in vivo, and (4) reverse cognitive deficits in animal models of dementia. Through screening studies, the compound now known as fosgonimeton-active metabolite (fosgo-AM) was identified by use of immunocytochemistry to be the most potent positive modulator of HGF/MET and was selected for further testing. Primary hippocampal neurons treated with fosgo-AM showed enhanced synaptogenesis and neurite outgrowth, supporting the neurotrophic effects of positive modulators of HGF/MET. Additionally, fosgo-AM protected against neurotoxic insults in primary cortical neuron cultures. In vivo, treatment with fosgo-AM rescued cognitive deficits in the rat scopolamine amnesia model of dementia. Although fosgo-AM demonstrated several procognitive effects in vitro and in vivo, a prodrug strategy was used to enhance the pharmacological properties of fosgo-AM, resulting in the development of fosgonimeton (ATH-1017). The effect of fosgonimeton on cognition was confirmed in a lipopolysaccharide (LPS)-induced neuroinflammatory mouse model of dementia. Together, the results of these studies support the potential of positive modulators of HGF/MET to be used as novel therapeutics and suggest the drug candidate fosgonimeton might protect against neurodegeneration and be therapeutic in the management of Alzheimer's disease and other types of dementia.
Identifiants
pubmed: 36538176
doi: 10.1007/s13311-022-01325-5
pii: 10.1007/s13311-022-01325-5
pmc: PMC10121968
doi:
Substances chimiques
Hepatocyte Growth Factor
67256-21-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
431-451Informations de copyright
© 2022. The Author(s).
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