title: Hydroxyethylamine-based inhibitors of BACE1: P₁-P₃ macrocyclization can improve potency, selectivity, and cell activity.
abstract: We describe a systematic study of how macrocyclization in the P₁-P₃ region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.
authors.affiliation: Medicinal Chemistry, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. lewpenn@icloud.com
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Steven R
authors.initials: SR
authors.lastname: Jordan
authors.forename: Holger
authors.initials: H
authors.lastname: Monenschein
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Bryant H
authors.initials: BH
authors.lastname: Yang
authors.forename: Qiufen M
authors.initials: QM
authors.lastname: Xue
authors.forename: Filisaty
authors.initials: F
authors.lastname: Vounatsos
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Stephen
authors.initials: S
authors.lastname: Wood
authors.forename: Martin
authors.initials: M
authors.lastname: Citron
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hitchcock
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhong
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002402:Cathepsin D / Q000378:metabolism; D018360:Crystallography, X-Ray; D005021:Ethylamines / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005021:Ethylamines; D047028:Macrocyclic Compounds; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D002402:Cathepsin D; C041564:ethylamine