Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors.

J N Cumming, T X Le, S Babu, C Carroll, X Chen, L Favreau, P Gaspari, T Guo, D W Hobbs, Y Huang, U Iserloh, M E Kennedy, R Kuvelkar, G Li, J Lowrie, N A McHugh, L Ozgur, J Pan, E M Parker, K Saionz, A W Stamford, C Strickland, D Tadesse, J Voigt, L Wang, Y Wu, L Zhang, Q Zhang

Index: Bioorg. Med. Chem. Lett. 18(11) , 3236-41, (2008)

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Abstract

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.