title: Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model.
abstract: In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
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: Gergley
authors.initials: G
authors.lastname: Tóth
authors.forename: Gary D
authors.initials: GD
authors.lastname: Probst
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sealy
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: David W G
authors.initials: DW
authors.lastname: Wone
authors.forename: Darren
authors.initials: D
authors.lastname: Dressen
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Brian T
authors.initials: BT
authors.lastname: Peterson
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Dora
authors.initials: D
authors.lastname: Kholodenko
authors.forename: Ruth N
authors.initials: RN
authors.lastname: Motter
authors.forename: Frédérique
authors.initials: F
authors.lastname: Bard
authors.forename: Pamela
authors.initials: P
authors.lastname: Santiago
authors.forename: Huifang
authors.initials: H
authors.lastname: Ni
authors.forename: David
authors.initials: D
authors.lastname: Chian
authors.forename: Ferdie
authors.initials: F
authors.lastname: Soriano
authors.forename: Tracy
authors.initials: T
authors.lastname: Cole
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Brigham
authors.forename: Karina
authors.initials: K
authors.lastname: Wong
authors.forename: Wes
authors.initials: W
authors.lastname: Zmolek
authors.forename: Erich
authors.initials: E
authors.lastname: Goldbach
authors.forename: Bhushan
authors.initials: B
authors.lastname: Samant
authors.forename: Linda
authors.initials: L
authors.lastname: Chen
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: David F
authors.initials: DF
authors.lastname: Nakamura
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: Ted A
authors.initials: TA
authors.lastname: Yednock
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
mesh_terms: D000478:Alkylation; D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007202:Indicators and Reagents; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D005021:Ethylamines; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human