Substituted 2-oxo-azepane derivatives are potent, orally active gamma-secretase inhibitors.
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.
Kitas
Eric A
EA
Pharma Division, Discovery Chemistry, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. eric_a.kitas@roche.com
Galley
Guido
G
Jakob-Roetne
Roland
R
Flohr
Alexander
A
Wostl
Wolfgang
W
Mauser
Harald
H
Alker
André M
AM
Czech
Christian
C
Ozmen
Laurence
L
David-Pierson
Pascale
P
Reinhardt
Dieter
D
Jacobsen
Helmut
H
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
D001381:Azepines; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases