title: Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.
abstract: Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.
authors.affiliation: Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: Gary D
authors.initials: GD
authors.lastname: Probst
authors.forename: Jose
authors.initials: J
authors.lastname: Aquino
authors.forename: Larry
authors.initials: L
authors.lastname: Fang
authors.forename: Louis
authors.initials: L
authors.lastname: Brogley
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sealy
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: John A
authors.initials: JA
authors.lastname: Tucker
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: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dappen
authors.forename: Gergley
authors.initials: G
authors.lastname: Tóth
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: Eric
authors.initials: E
authors.lastname: Brecht
authors.forename: Hu
authors.initials: H
authors.lastname: Pan
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Sukanto
authors.initials: S
authors.lastname: Sinha
authors.forename: Ted A
authors.initials: TA
authors.lastname: Yednock
authors.forename: Wes
authors.initials: W
authors.lastname: Zmolek
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D000440:Butanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000440:Butanols; D003514:Cyclohexylamines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human