Inhibitors of BACE for treating Alzheimer's disease: a fragment-based drug discovery story

•Hits from 12 BACE1 fragment screens clustered into amidines and amines.•The BACE1 key pharmacophore consists of a non-planar cyclic amidine.•Optimal substituent trajectories into the subpockets are required for high LE.•LE and in vivo biased optimization was critical to identify CNS active inhibitors.•Multiple fragment-derived BACE1 inhibitors have entered clinical trials.

Several fragment-based methods have been applied to the discovery of new lead sources for inhibitors of BACE1, an important therapeutic target for Alzheimer's disease. Among the most common fragment hits were various amidine-containing molecules in which the amidine engaged in discrete H-bond donor–acceptor interaction with the BACE1 catalytic dyad. Structure and medicinal chemistry knowledge-based optimization with emphasis on ligand efficiency resulted in identification of a key pharmacophore comprising a non-planar cyclic amidine scaffold directly attached to a phenyl group projecting into S1. This key pharmacophore is a common feature of known clinical candidates and has dominated the recent patent literature. A structural comparison of the non-planar cyclic amidine motif with other BACE1 pharmacophores highlights its uniqueness and distinct advantages.

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