1. Potent benzoazepinone γ-secretase modulators with improved bioavailability.
- Author
-
Methot JL, Fischer C, Li C, Rivkin A, Ahearn SP, Brown WC, Kattar S, Kelley E, Mampreian DM, Schell A, Rosenau A, Zhou H, Ball R, Deshmukh SV, Jeliazkova-Mecheva VV, Diaz D, Moy LY, Kenific CM, Moxham C, Shah S, Nuthall H, Szewczak AA, Hill A, Hughes B, Smotrov N, Munoz B, Miller TA, and Shearman MS
- Subjects
- Animals, Biological Availability, Mice, Mice, Transgenic, Rats, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases pharmacokinetics
- Abstract
The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aβ42 lowering maintained in both transgenic mouse and rat., (Copyright © 2015. Published by Elsevier Ltd.)
- Published
- 2015
- Full Text
- View/download PDF