title: Design and preparation of a potent series of hydroxyethylamine containing β-secretase inhibitors that demonstrate robust reduction of central β-amyloid.
abstract: A series of potent hydroxyethyl amine (HEA) derived inhibitors of β-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS β-amyloid (Aβ) in Sprague-Dawley rats following oral administration.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States. mmweiss@amgen.com
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Toni
authors.initials: T
authors.lastname: Williamson
authors.forename: Safura
authors.initials: S
authors.lastname: Babu-Khan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: James
authors.initials: J
authors.lastname: Brown
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Martin
authors.initials: M
authors.lastname: Citron
authors.forename: Michael D
authors.initials: MD
authors.lastname: Croghan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dineen
authors.forename: Joel
authors.initials: J
authors.lastname: Esmay
authors.forename: Russell F
authors.initials: RF
authors.lastname: Graceffa
authors.forename: Scott S
authors.initials: SS
authors.lastname: Harried
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hitchcock
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Horne
authors.forename: Hongbing
authors.initials: H
authors.lastname: Huang
authors.forename: Ronke
authors.initials: R
authors.lastname: Imbeah-Ampiah
authors.forename: Ted
authors.initials: T
authors.lastname: Judd
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kaller
authors.forename: Charles R
authors.initials: CR
authors.lastname: Kreiman
authors.forename: Daniel S
authors.initials: DS
authors.lastname: La
authors.forename: Vivian
authors.initials: V
authors.lastname: Li
authors.forename: Patricia
authors.initials: P
authors.lastname: Lopez
authors.forename: Steven
authors.initials: S
authors.lastname: Louie
authors.forename: Holger
authors.initials: H
authors.lastname: Monenschein
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.forename: Claire
authors.initials: C
authors.lastname: Rattan
authors.forename: Tisha
authors.initials: T
authors.lastname: San Miguel
authors.forename: E Allen
authors.initials: EA
authors.lastname: Sickmier
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wen
authors.forename: Stephen
authors.initials: S
authors.lastname: Wood
authors.forename: Qiufen
authors.initials: Q
authors.lastname: Xue
authors.forename: Bryant H
authors.initials: BH
authors.lastname: Yang
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001682:Biological Availability; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010446:Peptide Fragments / Q000378:metabolism*; D011487:Protein Conformation; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D004148:Dioxolanes; D005021:Ethylamines; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human