title: Structure guided P1' modifications of HEA derived β-secretase inhibitors for the treatment of Alzheimer's disease.
abstract: The synthesis and SAR of a series of BACE-1 hydroxyethyl amine inhibitors containing substitutions on a spirocyclobutyl moiety is described. Selectivity against cathepsin D, a related aspartyl protease with potential off target toxicity, and improved microsomal stability is exemplified.
authors.affiliation: Envoy Therapeutics, 555 Heritage Drive, Jupiter, FL 33458, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Monenschein
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Horne
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hitchcock
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhong
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000378:metabolism; D003198:Computer Simulation; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D005021:Ethylamines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D002402:Cathepsin D; C041564:ethylamine