BACE inhibitor NB-360 reveals strong reduction of amyloid-β generation, robust blockade of amyloid deposition and lowering of neuroinflammation in APP transgenic mice

Reducing the generation of β-amyloid peptide by inhibition of BACE-1 is currently investigated as a disease-modifying therapy for Alzheimer’s disease. First generations of peptidomimetic BACE-1 inhibitors showed low efficacy in vivo, mainly due to limited exposure in the brain. Recently, compounds with a cyclic amidine scaffold were found that overcome such limitations. We report here the characterization of NB-360, a compound derived from the 1,4-oxazine scaffold, which has excellent potency and brain penetration. NB-360 acutely inhibited the generation of Aβ40 and Aβ42 in APP51/16 mice, rats and dogs. Upon chronic treatment in APP51/16 transgenic mice, NB-360 completely blocked amyloid deposition. Furthermore, NB-360 significantly reduced signs of plaque-related brain inflammation, measured as the number of activated microglia cells and astrocytes. These data demonstrate the a highly attractive combination of drug-like properties in compound NB-360, and further indicate that BACE-1 inhibition, by preventing plaque deposition, may also prevent plaque-associated neuroinflammation