title: Synthesis and gamma-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres.
abstract: Two new APP substrate-based hydroxyethylene isosteres (AT and VI) were prepared and their dipeptide conjugates shown not to inhibit the gamma-secretase-mediated formation of either Abeta1-40 or Abeta1-42. The FG isostere and a des-hydroxy hydroxyethylene isostere also gave inactive compounds. Conversely, a number of compounds containing the intact substrate-unrelated Phe-Phe (FF) hydroxyethylene isostere were shown to be potent inhibitors (ED(50)=14-732 nM). These results show that the factors governing the substrate-based design of gamma-secretase inhibitors are more complicated than first thought.
authors.affiliation: Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. alan_nadin@merck.com
authors.forename: Alan
authors.initials: A
authors.lastname: Nadin
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Owens
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: Timothy
authors.initials: T
authors.lastname: Harrison
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010450:Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D005030:Ethylenes; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004151:Dipeptides; D005030:Ethylenes; D011480:Protease Inhibitors; C067254:hydroxyethylene; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human