title: Acylguanidines as small-molecule beta-secretase inhibitors.
abstract: BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. coledc@wyeth.com
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stock
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Condon
authors.forename: Lee D
authors.initials: LD
authors.lastname: Jennings
authors.forename: Ann
authors.initials: A
authors.lastname: Aulabaugh
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cowling
authors.forename: John W
authors.initials: JW
authors.lastname: Ellingboe
authors.forename: Kristi Y
authors.initials: KY
authors.lastname: Fan
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Harrison
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Steve
authors.initials: S
authors.lastname: Jacobsen
authors.forename: Guixan
authors.initials: G
authors.lastname: Jin
authors.forename: Laura
authors.initials: L
authors.lastname: Lin
authors.forename: Frank E
authors.initials: FE
authors.lastname: Lovering
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Mark L
authors.initials: ML
authors.lastname: Stahl
authors.forename: James
authors.initials: J
authors.lastname: Strand
authors.forename: Mohani N
authors.initials: MN
authors.lastname: Sukhdeo
authors.forename: Kristine
authors.initials: K
authors.lastname: Svenson
authors.forename: M James
authors.initials: MJ
authors.lastname: Turner
authors.forename: Erik
authors.initials: E
authors.lastname: Wagner
authors.forename: Junjun
authors.initials: J
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; D010455:Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases