Author/Authors :
Eric A. Kitas، نويسنده , , Guido Galley، نويسنده , , Roland Jakob-Roetne، نويسنده , , Alexander Flohr، نويسنده , , Wolfgang Wostl، نويسنده , , Harald Mauser، نويسنده , , André M. Alker، نويسنده , , Christian Czech، نويسنده , , Laurence Ozmen، نويسنده , , Pascale David-Pierson، نويسنده , , Dieter Reinhardt، نويسنده , , Helmut Jacobsen، نويسنده ,
Abstract :
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.
Keywords :
Alzheimer’s Disease , Amyloid A? lowering , Proteolytic activity , metabolism , In Vivo , ?-Secretase
