title: Difluorophenylglycinols as new modulators of proteolytic processing of amyloid precursor proteins.
abstract: Synthesis and evaluation of difluorophenylglycinols as new modulators of proteolytic processing of the amyloid-β precursor proteins for Alzheimer's therapies were described. A range of N-substituted (R)- and (S)-difluorophenylglycinols, structured on the amino alcohol framework, were explored by incorporating the arylsulfonyl moieties and various N-substituents. Evans' chiral auxiliary strategy was employed for the asymmetric synthesis of these enantiomeric difluorophenylglycinols. Compounds with effects on the γ-secretase inhibition and ERK-mediated signaling pathways were evaluated on cell-based assays. Among them, N-cyclopropylmethyl derivatives R-12c and R-13c showed modest γ-secretase inhibition as well as ERK-dependent activation.
authors: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
authors: Chia-Yu
authors: CY
authors: Chen
authors: Yung-Feng
authors: YF
authors: Liao
authors: Ming-Yun
authors: MY
authors: Chang
authors: Ming-Kuan
authors: MK
authors: Hu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D004789:Enzyme Activation; D004983:Ethanolamines / Q000138:chemical synthesis / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D004983:Ethanolamines; D011480:Protease Inhibitors; C005332:N-phenylethanolamine; D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; Asymmetric synthesis; ERK-mediated signaling; γ-Secretase