title: Purine derivatives as potent gamma-secretase modulators.
abstract: The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.
authors.affiliation: Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. alexey_rivkin@merck.com
authors.forename: Alexey
authors.initials: A
authors.lastname: Rivkin
authors.forename: Sean P
authors.initials: SP
authors.lastname: Ahearn
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Chichetti
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Hamblett
authors.forename: Yudith
authors.initials: Y
authors.lastname: Garcia
authors.forename: Michelle
authors.initials: M
authors.lastname: Martinez
authors.forename: Jed L
authors.initials: JL
authors.lastname: Hubbs
authors.forename: Michael H
authors.initials: MH
authors.lastname: Reutershan
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Daniels
authors.forename: Phieng
authors.initials: P
authors.lastname: Siliphaivanh
authors.forename: Karin M
authors.initials: KM
authors.lastname: Otte
authors.forename: Chaomin
authors.initials: C
authors.lastname: Li
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosenau
authors.forename: Laura M
authors.initials: LM
authors.lastname: Surdi
authors.forename: Joon
authors.initials: J
authors.lastname: Jung
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Hughes
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Crispino
authors.forename: George N
authors.initials: GN
authors.lastname: Nikov
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Moxham
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Shah
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.forename: Candia M
authors.initials: CM
authors.lastname: Kenific
authors.forename: Flobert
authors.initials: F
authors.lastname: Tanga
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.forename: Paula
authors.initials: P
authors.lastname: Andrade
authors.forename: Minilik H
authors.initials: MH
authors.lastname: Angagaw
authors.forename: Nirah H
authors.initials: NH
authors.lastname: Shomer
authors.forename: Thomas
authors.initials: T
authors.lastname: Miller
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051880:Receptors, Notch / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011687:Purines; D051880:Receptors, Notch; C538897:amyloid beta-protein (40-42); D053829:Amyloid Precursor Protein Secretases