title: Discovery of small molecular (D)-leucinamides as potent, Notch-sparing γ-secretase modulators.
abstract: Structural optimization of the prior lead 3 led to the small molecular (D)-leucinamides with potent modulating activity and Notch-sparing selectivity on the proteolytic processing of amyloid-β precursor proteins. The N-(R)-epoxypropyl analog 10c exhibited potent γ-secretase modulation compared to DAPT and showed substantial substrate selection for APP cleavage over Notch cleavage, while N-(2-fluoro)benzyl analog 10e showed the most potent γ-secretase inhibition with dull selectivity. The exceptional suppression of ERK-mediated activation suggested that these potent γ-secretase modulators may adapt an alternative pathway to prominently induce the differential inhibition of C99 cleavage by γ-secretase.
authors.affiliation: Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Liao
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Tang
authors.affiliation: Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Ming-Yun
authors.initials: MY
authors.lastname: Chang
authors.affiliation: Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Bo-Jeng
authors.initials: BJ
authors.lastname: Wang
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan. Electronic address: hmk@ndmctsgh.edu.tw.
authors.forename: Ming-Kuan
authors.initials: MK
authors.lastname: Hu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D054852:Small Molecule Libraries; D053829:Amyloid Precursor Protein Secretases; D007930:Leucine; C013086:leucinamide
keywords: Alzheimer's disease; Amyloid-β precursor protein; Notch-sparing selectivity; γ-Secretase