Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR

We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5–19). In conjunction with four fixed residues at the P1 (Phe), P1′ (Ala), P2′ (Val), and P2′ cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC50=45 nM) and cellular activity (IC50=0.4 μM).