S-872881: A Fused Oxazine-Based Potent BACE1 Inhibitor with High In Vivo Selectivity over BACE2 and Reduced Risk of Liver and Cardiovascular Toxicity for Maintenance Therapy Following Immunotherapy

Abstract

BACE1 inhibition is an attractive approach for maintenance therapy after anti-Aβ antibody treatment in Alzheimer’s disease. Unfortunately, clinical BACE1 inhibitors, such as atabecestat, exhibited hepatotoxicity, cognitive impairment, or cardiotoxicity in clinical trials, thus preventing their use for maintenance therapy. Hence, we focused our efforts on finding BACE1 inhibitors with mitigated adverse effects. As hepatotoxicity could be caused by reactive metabolites derived from the thiazine ring, it was replaced with oxazine. To avoid cognitive impairment, we aimed at improving selectivity over BACE2. These efforts led to the design of THP-fused oxazine derivatives that can recognize the difference in the flap regions as well as achieve a minimal energy difference between an active and the most stable conformation. The newly discovered S-872881 exhibits >100-fold binding selectivity, significantly inhibits Aβ production in dogs without BACE2 inhibition, and displays a sufficient safety margin in vivo.