title: Fluorinated piperidine acetic acids as gamma-secretase modulators.
abstract: We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.
authors.affiliation: Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. matthew_stanton@merck.com
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Stanton
authors.forename: Jed
authors.initials: J
authors.lastname: Hubbs
authors.forename: David
authors.initials: D
authors.lastname: Sloman
authors.forename: Christopher
authors.initials: C
authors.lastname: Hamblett
authors.forename: Paula
authors.initials: P
authors.lastname: Andrade
authors.forename: Minilik
authors.initials: M
authors.lastname: Angagaw
authors.forename: Grace
authors.initials: G
authors.lastname: Bi
authors.forename: Regina M
authors.initials: RM
authors.lastname: Black
authors.forename: Jamie
authors.initials: J
authors.lastname: Crispino
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.forename: Eric
authors.initials: E
authors.lastname: Fan
authors.forename: Georgia
authors.initials: G
authors.lastname: Farris
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Hughes
authors.forename: Candia M
authors.initials: CM
authors.lastname: Kenific
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: George
authors.initials: G
authors.lastname: Nikov
authors.forename: Peter
authors.initials: P
authors.lastname: Sajonz
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Shah
authors.forename: Nirah
authors.initials: N
authors.lastname: Shomer
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Flobert
authors.initials: F
authors.lastname: Tanga
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Tudge
authors.forename: Mark
authors.initials: M
authors.lastname: Shearman
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003979:Diazonium Compounds / Q000737:chemistry; D004195:Disease Models, Animal; D005461:Fluorine / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: D000085:Acetates; D016229:Amyloid beta-Peptides; D003979:Diazonium Compounds; D010446:Peptide Fragments; D010880:Piperidines; D051880:Receptors, Notch; C075222:amyloid beta-protein (1-42); D005461:Fluorine; C408750:selectfluor; D053829:Amyloid Precursor Protein Secretases