Small-molecule BACE1 inhibitors: a patent literature review (2011 to 2020).

Despite an increasingly crowded IP situation, significant progress was made using highly complex chemistry in avoiding toxicity liabilities, with BACE1/BACE2 selectivity being the most remarkable achievement. However, clinical trial data suggest on-target toxicity is likely a contributing factor, which implies the only potential future of BACE1 inhibitors lies in careful titration of highly selective compounds in early populations where the amyloid burden is still minimal as prophylactic therapy, or as an affordable oral maintenance therapy following amyloid-clearing therapies.