Discovery of an orally efficaceous 4-phenoxypyrrolidine-based BACE-1 inhibitor

Abstract Based on a lead compound identified from the patent literature, we developed patentably novel BACE-1 inhibitors by introducing a cyclic amine scaffold as embodied by 1a and 1b . Extensive SAR studies assessed a variety of isophthalamide replacements including substituted pyrrolidinones and ultimately led to the identification of 11 . Due to its favorable overall profile, 11 has been extensively profiled in various in vivo settings.