title: Discovery of gamma-secretase inhibitors efficacious in a transgenic animal model of Alzheimer's disease.
abstract: Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.
authors.affiliation: Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Theodros
authors.initials: T
authors.lastname: Asberom
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bara
authors.forename: John W
authors.initials: JW
authors.lastname: Clader
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.forename: Hubert B
authors.initials: HB
authors.lastname: Josien
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McPhail
authors.forename: Amin A
authors.initials: AA
authors.lastname: Nomeir
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Murali
authors.initials: M
authors.lastname: Rajagopalan
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.forename: Gwendolyn T
authors.initials: GT
authors.lastname: Wong
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Pissarnitski
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D053829:Amyloid Precursor Protein Secretases