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

• Published in: Bioorganic & medicinal chemistry letters 2004-01, Vol.14 (1), p.239-243
• Main Authors: Lamar, Jason, Hu, Jingdan, Bueno, Ana Belen, Yang, Hsiu-Chiung, Guo, Deqi, Copp, James D., McGee, James, Gitter, Bruce, Timm, David, May, Patrick, McCarthy, James, Chen, Shu-Hui
• Format: Article
• Language: English
• Subjects: Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Biological and medical sciences; Cell Line; Dipeptides - chemical synthesis; Dipeptides - toxicity; Endopeptidases - metabolism; Humans; Medical sciences; Molecular Mimicry; Neuropharmacology; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - toxicity; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.09.084

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 (IC 50=45 nM) and cellular activity (IC 50=0.4 μM). We describe herein the syntheses and evaluation of a series of Phe*-Ala-based BACE inhibitors. The most promising inhibitors demonstrated very good enzyme and cellular activity.