title: Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors.
abstract: Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. joshua_close@merck.com
authors.forename: Joshua
authors.initials: J
authors.lastname: Close
authors.forename: Richard
authors.initials: R
authors.lastname: Heidebrecht
authors.forename: John
authors.initials: J
authors.lastname: Hendrix
authors.forename: Chaomin
authors.initials: C
authors.lastname: Li
authors.forename: Ben
authors.initials: B
authors.lastname: Munoz
authors.forename: Laura
authors.initials: L
authors.lastname: Surdi
authors.forename: Solomon
authors.initials: S
authors.lastname: Kattar
authors.forename: Paul
authors.initials: P
authors.lastname: Tempest
authors.forename: Paul
authors.initials: P
authors.lastname: Moses
authors.forename: Xiaoliu
authors.initials: X
authors.lastname: Geng
authors.forename: Bethany
authors.initials: B
authors.lastname: Hughes
authors.forename: Nadya
authors.initials: N
authors.lastname: Smotrov
authors.forename: Chris
authors.initials: C
authors.lastname: Moxham
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chapnick
authors.forename: Ilona
authors.initials: I
authors.lastname: Kariv
authors.forename: George
authors.initials: G
authors.lastname: Nikov
authors.forename: Julie Elizabeth
authors.initials: JE
authors.lastname: Burke
authors.forename: Sujal
authors.initials: S
authors.lastname: Deshmukh
authors.forename: Valentina
authors.initials: V
authors.lastname: Jeliazkova-Mecheva
authors.forename: John Kevin
authors.initials: JK
authors.lastname: Leach
authors.forename: Damaris
authors.initials: D
authors.lastname: Diaz
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Ziping
authors.initials: Z
authors.lastname: Yang
authors.forename: Gloria
authors.initials: G
authors.lastname: Kwei
authors.forename: Lily
authors.initials: L
authors.lastname: Moy
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Shah
authors.forename: Flobert
authors.initials: F
authors.lastname: Tanga
authors.forename: Candia
authors.initials: C
authors.lastname: Kenefic
authors.forename: Dan
authors.initials: D
authors.lastname: Savage
authors.forename: Mark
authors.initials: M
authors.lastname: Shearman
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McNevin
authors.forename: Amanda
authors.initials: A
authors.lastname: Markarewicz
authors.forename: Thomas
authors.initials: T
authors.lastname: Miller
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D010446:Peptide Fragments / Q000096:biosynthesis; D010880:Piperidines / Q000737:chemistry*
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases