title: Novel orally active, dibenzazepinone-based gamma-secretase inhibitors.
abstract: Structural modifications of the gamma-secretase inhibitor, LY411575, led to a malonamide analogue (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compound (R/S),(S)-13 with high in vitro activity (IC(50)=1.7 nM), and in vivo activity after oral administration (MED=3 mg/kg). Further modifications gave an equipotent carbamate analogue 14 with improved molecular properties.
authors.affiliation: Pharma Division, Discovery Chemistry, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. jens-uwe.peters@roche.com
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Peters
authors.forename: Guido
authors.initials: G
authors.lastname: Galley
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.forename: Pascale
authors.initials: P
authors.lastname: David-Pierson
authors.forename: Eric A
authors.initials: EA
authors.lastname: Kitas
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D053719:Tandem Mass Spectrometry
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine