Rational design and synthesis of potent dibenzazepine motifs as beta-secretase inhibitors.

We have identified small-molecule dibenzazepine inhibitors of beta-secretase (BACE1). These BACE1 inhibitors possess two key salient features. The first is a seven-membered heterocyclic ring fused to two aromatic rings representing the P3-P2 residues. The second is an amide and/or amide bioisostere representing the P1' residue. Rational optimization led to the identification of potent analogues, such as 10 (K(I) = 211 nM).