Abstract
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 P 4 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.
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