title: 4-substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors.
abstract: The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice).
authors.affiliation: Department of Medicinal Chemistry, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. ian_churcher@merck.com
authors.forename: Ian
authors.initials: I
authors.lastname: Churcher
authors.forename: Dirk
authors.initials: D
authors.lastname: Beher
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Best
authors.forename: José L
authors.initials: JL
authors.lastname: Castro
authors.forename: Earl E
authors.initials: EE
authors.lastname: Clarke
authors.forename: Amy
authors.initials: A
authors.lastname: Gentry
authors.forename: Timothy
authors.initials: T
authors.lastname: Harrison
authors.forename: Laure
authors.initials: L
authors.lastname: Hitzel
authors.forename: Euan
authors.initials: E
authors.lastname: Kay
authors.forename: Sonia
authors.initials: S
authors.lastname: Kerrad
authors.forename: Huw D
authors.initials: HD
authors.lastname: Lewis
authors.forename: Pablo
authors.initials: P
authors.lastname: Morentin-Gutierrez
authors.forename: Russell
authors.initials: R
authors.lastname: Mortishire-Smith
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Oakley
authors.forename: Michael
authors.initials: M
authors.lastname: Reilly
authors.forename: Duncan E
authors.initials: DE
authors.lastname: Shaw
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
authors.forename: Martin R
authors.initials: MR
authors.lastname: Teall
authors.forename: Susie
authors.initials: S
authors.lastname: Williams
authors.forename: Jonathan D J
authors.initials: JD
authors.lastname: Wrigley
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000187:drug effects; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010446:Peptide Fragments / Q000187:drug effects; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D013450:Sulfones; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse