Pharmacological characterization of the novel γ-secretase modulator AS2715348, a potential therapy for Alzheimer's disease, in rodents and nonhuman primates

• Published in: Neuropharmacology 2014-04, Vol.79, p.412-419
• Main Authors: Mitani, Yasuyuki, Akashiba, Hiroki, Saita, Kyoko, Yarimizu, Junko, Uchino, Hiroshi, Okabe, Mayuko, Asai, Makoto, Yamasaki, Shingo, Nozawa, Takashi, Ishikawa, Noritoshi, Shitaka, Yoshitsugu, Ni, Keni, Matsuoka, Nobuya
• Format: Article
• Language: English
• Subjects: Acetates - adverse effects; Acetates - pharmacokinetics; Acetates - pharmacology; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; Amyloid-β; Animals; Brain - drug effects; Brain - metabolism; Cell Line, Tumor; Cognition; Cognition - drug effects; Cyclohexylamines - adverse effects; Cyclohexylamines - pharmacokinetics; Cyclohexylamines - pharmacology; Cynomolgus; Disease Models, Animal; Female; Humans; Macaca fascicularis; Male; Mice; Mice, Transgenic; Molecular Structure; Neuroprotective Agents - adverse effects; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Nootropic Agents - adverse effects; Nootropic Agents - chemistry; Nootropic Agents - pharmacology; Peptide Fragments - metabolism; Primates; Rats; Rats, Sprague-Dawley; Receptors, Notch - metabolism; γ-Secretase
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.12.013

γ-Secretase is the enzyme responsible for the intramembranous proteolysis of various substrates, such as amyloid precursor protein (APP) and Notch. Amyloid-β peptide 42 (Aβ42) is produced through the sequential proteolytic cleavage of APP by β- and γ-secretase and causes the synaptic dysfunction associated with memory impairment in Alzheimer's disease. Here, we identified a novel cyclohexylamine-derived γ-secretase modulator, {(1R*,2S*,3R*)-3-[(cyclohexylmethyl)(3,3-dimethylbutyl)amino]-2-[4-(trifluoromethyl)phenyl]cyclohexyl}acetic acid (AS2715348), that may inhibit this pathological response. AS2715348 was seen to reduce both cell-free and cellular production of Aβ42 without increasing levels of APP β-carboxyl terminal fragment or inhibiting Notch signaling. Additionally, the compound increased Aβ38 production, suggesting a shift of the cleavage site in APP. The inhibitory potency of AS2715348 on endogenous Aβ42 production was similar across human, mouse, and rat cells. Oral administration with AS2715348 at 1 mg/kg and greater significantly reduced brain Aβ42 levels in rats, and no Notch-related toxicity was observed after 28-day treatment at 100 mg/kg. Further, AS2715348 significantly ameliorated cognitive deficits in APP-transgenic Tg2576 mice. Finally, AS2715348 significantly reduced brain Aβ42 levels in cynomolgus monkeys. These findings collectively show the promise for AS2715348 as a potential disease-modifying drug for Alzheimer's disease. •We identified a novel cyclohexylamine-derived γ-secretase modulator AS2715348.•AS2715348 significantly reduced brain Aβ42 levels in rats and cynomolgus monkeys.•AS2715348 significantly ameliorated cognitive deficits in Tg2576 AD model mice.•Chronic high dosing of AS2715348 showed no Notch-related toxicity in rats.•AS2715348 has potential as a disease-modifying drug for Alzheimer's disease.