Design and synthesis of highly active Alzheimer’s β-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability

Recently, we reported potent and small-sized BACE1 inhibitors KMI-358 and KMI-370 in which the Glu residue is replaced by a β-N-oxalyl-DAP (l-α,β-diaminopropionyl) residue at the P4 position. The β-N-oxalyl-DAP group is important for enhancing BACE1 inhibitory activity, but these inhibitors isomerized to α-N-oxalyl-DAP derivatives in solvents. Hence, we used a tetrazole moiety as a bioisostere of the free carboxylic acid of the oxalyl group. KMI-420 and KMI-429, containing a tetrazole ring, showed improved stability and potent enzyme inhibitory activity.