title: Substituted 2-oxo-azepane derivatives are potent, orally active gamma-secretase inhibitors.
abstract: A hydroxamic acid screening hit 1 was elaborated to 5,5-dimethyl-2-oxoazepane derivatives exhibiting low nanomolar inhibition of gamma-secretase, a key proteolytic enzyme involved in Alzheimer's disease. Early ADME data showed a high metabolic clearance for the geminal dimethyl analogs which could be overcome by replacement with the bioisosteric geminal difluoro group. Synthesis and structure-activity relationship are discussed and in vivo active compounds are presented.
authors.affiliation: Pharma Division, Discovery Chemistry, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. eric_a.kitas@roche.com
authors.forename: Eric A
authors.initials: EA
authors.lastname: Kitas
authors.forename: Guido
authors.initials: G
authors.lastname: Galley
authors.forename: Roland
authors.initials: R
authors.lastname: Jakob-Roetne
authors.forename: Alexander
authors.initials: A
authors.lastname: Flohr
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wostl
authors.forename: Harald
authors.initials: H
authors.lastname: Mauser
authors.forename: André M
authors.initials: AM
authors.lastname: Alker
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Pascale
authors.initials: P
authors.lastname: David-Pierson
authors.forename: Dieter
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases