Novel orally active, dibenzazepinone-based γ-secretase inhibitors

…, C Czech, P David-Pierson, EA Kitas, L Ozmen

Index: Peters, Jens-Uwe; Galley, Guido; Jacobsen, Helmut; Czech, Christian; David-Pierson, Pascale; Kitas, Eric A.; Ozmen, Laurence Bioorganic and Medicinal Chemistry Letters, 2007 , vol. 17, # 21 p. 5918 - 5923

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Citation Number: 28

Abstract

Structural modifications of the γ-secretase inhibitor, LY411575, led to a malonamide analogue (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compound (R/S),(S)-13 with high in vitro activity (IC50= 1.7 nM), and in vivo activity after oral administration (MED= 3mg/kg). Further modifications ...