title: 2,6-Disubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors.
abstract: A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
authors.affiliation: Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. Dmitri.Pisaarnitski@spcorp.com
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Pissarnitski
authors.forename: Theodros
authors.initials: T
authors.lastname: Asberom
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bara
authors.forename: Alex V
authors.initials: AV
authors.lastname: Buevich
authors.forename: John W
authors.initials: JW
authors.lastname: Clader
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Henry S
authors.initials: HS
authors.lastname: Guzik
authors.forename: Hubert B
authors.initials: HB
authors.lastname: Josien
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: McEwan
authors.forename: Brian A
authors.initials: BA
authors.lastname: McKittrick
authors.forename: Terry L
authors.initials: TL
authors.lastname: Nechuta
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Lisa
authors.initials: L
authors.lastname: Sinning
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Smith
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.forename: Henry A
authors.initials: HA
authors.lastname: Vaccaro
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Voigt
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases