title: Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors.
abstract: This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA.
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Lindsley
authors.forename: Keith P
authors.initials: KP
authors.lastname: Moore
authors.forename: Hemaka A
authors.initials: HA
authors.lastname: Rajapakse
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Young
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kuo
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.forename: Eric A
authors.initials: EA
authors.lastname: Price
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Guy R
authors.initials: GR
authors.lastname: Seabrook
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Nicole T
authors.initials: NT
authors.lastname: Pudvah
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Hochman
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D003500:Cyclization; D015195:Drug Design; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human