title: Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.
abstract: The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.
authors.affiliation: Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Ng
authors.forename: Minghua
authors.initials: M
authors.lastname: Sun
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Gary D
authors.initials: GD
authors.lastname: Probst
authors.forename: Varghese
authors.initials: V
authors.lastname: John
authors.forename: Lawrence Y
authors.initials: LY
authors.lastname: Fang
authors.forename: Michel
authors.initials: M
authors.lastname: Maillard
authors.forename: Andrea
authors.initials: A
authors.lastname: Gailunas
authors.forename: Louis
authors.initials: L
authors.lastname: Brogley
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
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: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: Wes
authors.initials: W
authors.lastname: Zmolek
authors.forename: David
authors.initials: D
authors.lastname: Nakamura
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: Ted A
authors.initials: TA
authors.lastname: Yednock
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D002478:Cells, Cultured; D002839:Chromans / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D002839:Chromans; D004791:Enzyme Inhibitors; D005021:Ethylamines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; BACE-1; Beta-secratase inhibitor; Cat-D; Chromane; Hydroxyethylamine