In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer's Disease.
Alzheimer's disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD. In this study, we report on the in vivo pharmacological characterization of ARN14140, a new chemical entity, which was obtained through a multi-target structure-activity relationship campaign, and which showed a balanced inhibiting profile against the acetylcholinesterase enzyme and the NMDA receptor. Based on the initial promising biochemical data, ARN14140 is here studied in mice treated with the amyloidogenic fragment 25-35 of the amyloid-β peptide, a consolidated non-transgenic AD model. Sub-chronically treating animals with ARN14140 leads to a prevention of the cognitive impairment and of biomarker levels connected to neurodegeneration, demonstrating its neuroprotective potential as new AD agent.
Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.
Angelo M
AM
Reggiani
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Elena
E
Simoni
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Roberta
R
Caporaso
Amylgen, Montferrier-sur-Lez, France.
Johann
J
Meunier
Amylgen, Montferrier-sur-Lez, France.
Emeline
E
Keller
Amylgen, Montferrier-sur-Lez, France.|INSERM U1198, Montpellier, France.|University of Montpellier, Montpellier, France.|EPHE, Paris, France.
Tangui
T
Maurice
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Anna
A
Minarini
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Michela
M
Rosini
Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.|Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Andrea
A
Cavalli
D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005702:Galantamine / Q000494:pharmacology*; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D005702:Galantamine; D008559:Memantine