P01
γ-Secretase Modulators with Reduced
Lipophilicity and Reduced Liver Toxicity
F. P. Bischoff, T. Wu, F. J. R. Rombouts, D. Berthelot, D. Oehlrich, M. A. J. De Cleyn, A. I. Velter, M. Surkyn, S. Van Brandt,
A. A. Trabanco, G. Macdonald, M. Mercken, H. J. M. Gijsen
Neuroscience Medicinal Chemistry, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium
Gamma secretase modulators (GSMs) reduce the production of the toxic A42
peptides in favor of the shorter and less amyloidogenic A38/A37 peptides.
Most of the known GSMs are suffering from sub-optimal physico-chemical properties
especially high lipophilicity, high molecular weight, high aromaticity and several of
them have demonstrated liver toxicity.
We disclose the evolution of a simple amide series to conformationally restricted
triazolo-piperidines/-morpholines that turned out to be potent in vitro and in vivo
GSMs with reduced aromaticity and lipophilicity as well as reduced liver toxicity.
A42 IC50 = 87 nM
cLogP 4.8, MW 420
A42 IC50 = 2630 nM
cLogP 3.8, MW 353
A42 IC50 = 65 nM
cLogP 3.1, MW 472