title: Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1).
abstract: We describe the development of cell-permeable beta-secretase inhibitors that demonstratively inhibit the production of the secreted amino terminal fragment of an artificial amyloid precursor protein in cell culture. In addition to potent inhibition in a cell-based assay (IC50 < 100 nM), these inhibitors display impressive selectivity against other biologically relevant aspartyl proteases.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. shawn_stachel@merck.com
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Steele
authors.forename: Kristen G
authors.initials: KG
authors.lastname: Jones
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Loutzenhiser
authors.forename: Alison R
authors.initials: AR
authors.lastname: Gregro
authors.forename: Hemaka A
authors.initials: HA
authors.lastname: Rajapakse
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Janet E
authors.initials: JE
authors.lastname: Lineberger
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pietrak
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chen-Dodson
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kuo
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D005021:Ethylamines; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases