Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors

Guided by structure-based design, we synthesized two novel series of potent inhibitors of BACE1 and generated extensive SAR around both the prime and non-prime side binding pockets. The key feature of both series is a cyclic amine motif specifically crafted to achieve interactions with both the flap and with the S2′ pocket.

Graphical abstractTwo novel, potent cyclic amine motifs for BACE1 inhibitors are described, along with their SAR in both the non-prime and prime subsites.Figure optionsDownload full-size imageDownload as PowerPoint slide