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Bioorg. Med. Chem. Lett. · Jan 2008
Substituted 2-oxo-azepane derivatives are potent, orally active gamma-secretase inhibitors.
- Eric A Kitas, Guido Galley, Roland Jakob-Roetne, Alexander Flohr, Wolfgang Wostl, Harald Mauser, André M Alker, Christian Czech, Laurence Ozmen, Pascale David-Pierson, Dieter Reinhardt, and Helmut Jacobsen.
- Pharma Division, Discovery Chemistry, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. eric_a.kitas@roche.com
- Bioorg. Med. Chem. Lett. 2008 Jan 1; 18 (1): 304-8.
AbstractA 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.
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