Design and Preparation of a Potent Series of Hydroxyethylamine Containing 尾-Secretase Inhibitors That Demonstrate Robust Reduction of Central 尾-Amyloid
A series of potent hydroxyethyl amine (HEA) derived inhibitors of 尾-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS 尾-amyloid (A尾) in Sprague鈥揇awley rats following oral administration.