title: Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer's disease.
abstract: The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Nampally
authors.initials: N
authors.lastname: Sreenivasachary
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Heiko
authors.initials: H
authors.lastname: Kroth
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Benderitter
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Hamel
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Varisco
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: David T
authors.initials: DT
authors.lastname: Hickman
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Froestl
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland. Electronic address: andreas.muhs@acimmune.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*
chemical_list: C023422:7-azaindole dimer; D016229:Amyloid beta-Peptides; D007211:Indoles; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Azaindole derivatives; Aβ aggregation; Indole derivatives; Inhibitors; Structure-activity relationship