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 0 (Ala), P2 0 (Val), and P2 0 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=0.4mM). # 2003 Elsevier Ltd. All rights reserved.