Iminoheterocycle as a druggable motif: BACE1 inhibitors and beyond

Beta-secretase 1 (BACE1) is a central nervous system (CNS) aspartyl protease required for production of amyloid beta (Aβ) peptides. Brain-penetrant BACE1 inhibitors are central to test the 'amyloid hypothesis', which suggests that a reduction of Aβ species in the CNS would halt or even reverse Alzheimer's disease. Discovery of the iminoheterocycle class of BACE1 inhibitors (which show robust efficacy in reduction of CNS Aβ species in animal models) marked an important milestone. These discoveries arose independently from multiple research laboratories that took different paths to end at the same scaffolds. These druggable motifs should be applicable to other aspartyl proteases of therapeutic importance and also to other protein targets involving crucial interactions with carboxylic acid side chains. Here, a comparison of these approaches to BACE1 discovery will showcase how it is important to pay attention to the intrinsic physicochemical properties of the lead series, even at the very early stage of drug discovery.