title: Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents.
abstract: Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.
authors.affiliation: Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sealy
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: Luke
authors.initials: L
authors.lastname: Tso
authors.forename: Gary D
authors.initials: GD
authors.lastname: Probst
authors.forename: Jose
authors.initials: J
authors.lastname: Aquino
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Jagodzinska
authors.forename: Darren
authors.initials: D
authors.lastname: Dressen
authors.forename: David W G
authors.initials: DW
authors.lastname: Wone
authors.forename: Louis
authors.initials: L
authors.lastname: Brogley
authors.forename: Varghese
authors.initials: V
authors.lastname: John
authors.forename: Jay S
authors.initials: JS
authors.lastname: Tung
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pleiss
authors.forename: John A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dappen
authors.forename: Gergely
authors.initials: G
authors.lastname: Toth
authors.forename: Hu
authors.initials: H
authors.lastname: Pan
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Jim
authors.initials: J
authors.lastname: Miller
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Sukanto
authors.initials: S
authors.lastname: Sinha
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human