title: Pharmacological characterization of the novel γ-secretase modulator AS2715348, a potential therapy for Alzheimer's disease, in rodents and nonhuman primates.
abstract: 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.
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: yasuyuki.mitani@astellas.com.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Mitani
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Akashiba
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Saita
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yarimizu
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchino
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Okabe
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Asai
authors.affiliation: Chemistry Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nozawa
authors.affiliation: Drug Safety Research Laboratories, Astellas Pharma Inc., Osaka, Japan.
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Ishikawa
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Shitaka
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Keni
authors.initials: K
authors.lastname: Ni
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000085:Acetates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D003071:Cognition / Q000187:drug effects; D003514:Cyclohexylamines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D018697:Nootropic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: C000593233:3-((cyclohexylmethyl)(3,3-dimethylbutyl)amino)-2-(4-(trifluoromethyl)phenyl)cyclohexyl)acetic acid; C545487:APP protein, human; D000085:Acetates; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003514:Cyclohexylamines; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010446:Peptide Fragments; D051880:Receptors, Notch; C078639:amyloid beta-protein (1-38); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; Amyloid-β; Cognition; γ-Secretase