title: Macrocyclic inhibitors of beta-secretase: functional activity in an animal model.
abstract: A macrocyclic inhibitor of beta-secretase was designed by covalently cross-linking the P1 and P3 side chains of an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improved potency and physical properties when compared to the initial lead structures. More importantly, these macrocyclic inhibitors also displayed in vivo amyloid lowering when dosed in a murine model.
authors.affiliation: Department of Medicinal Chemistry, Biological Chemistry, Molecular Systems and Structural Biology Merck Research Laboratories, Post Office 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: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Eric A
authors.initials: EA
authors.lastname: Price
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Michelle
authors.initials: M
authors.lastname: Crouthamel
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pietrak
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Janet
authors.initials: J
authors.lastname: Lineberger
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Joan
authors.initials: J
authors.lastname: Ellis
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Timothy
authors.initials: T
authors.lastname: Allison
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000577:Amides / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008968:Molecular Conformation; D010795:Phthalic Acids / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D047028:Macrocyclic Compounds; D010795:Phthalic Acids; D011480:Protease Inhibitors; C059768:isophthalate; D053829:Amyloid Precursor Protein Secretases