Substituted 2-oxo-azepane derivatives are potent, orally active γ-secretase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 1; pp. 304 - 308
• Main Authors: Kitas, Eric A., Galley, Guido, Jakob-Roetne, Roland, Flohr, Alexander, Wostl, Wolfgang, Mauser, Harald, Alker, André M., Czech, Christian, Ozmen, Laurence, David-Pierson, Pascale, Reinhardt, Dieter, Jacobsen, Helmut
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 2008; Elsevier
• Subjects: Alzheimer’s disease; Amyloid Aβ lowering; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; Biological and medical sciences; Humans; Hydroxamic Acids - chemistry; In vivo; Medical sciences; Metabolism; Mice; Mice, Transgenic; Models, Molecular; Neuropharmacology; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Proteolytic activity; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship; γ-Secretase; Proteolytic activity; In vivo; Alzheimer’s disease; Metabolism; γ-Secretase; Amyloid Aβ lowering; Alzheimer disease; Lactam; Pyridine derivatives; Thiophene derivatives; Structure activity relation; Proteolysis; Chlorine Organic compounds; Degenerative disease; Aspartic endopeptidases; Alzheimer's disease; Nervous system diseases; Sulfonamide; Absorption Distribution Metabolisme Excretion; Enzyme; Rodentia; Oral administration; Antialzheimer agent; In vitro; Amyloid precursor protein; Cerebral disorder; Peptidases; Vertebrata; Mammalia; Mouse; β Amyloid protein; Animal; Central nervous system disease; Hydrolases; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.10.074

A hydroxamic acid screening hit was elaborated to 5,5-difluoro-2-oxoazepane derivatives exhibiting low nanomolar inhibition of γ-secretase, a key proteolytic enzyme involved in Alzheimer’s disease (AD). Oral activity was observed in a transgenic mouse model for AD. A hydroxamic acid screening hit 1 was elaborated to 5,5-dimethyl-2-oxoazepane derivatives exhibiting low nanomolar inhibition of γ-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.