Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads

• Published in: Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (10), p.3158-3160
• Main Authors: Huang, Yifang, Strobel, Eric D., Ho, Chih Y., Reynolds, Charles H., Conway, Kelly A., Piesvaux, Jennifer A., Brenneman, Douglas E., Yohrling, George J., Moore Arnold, H., Rosenthal, Daniel, Alexander, Richard S., Tounge, Brett A., Mercken, Marc, Vandermeeren, Marc, Parker, Michael H., Reitz, Allen B., Baxter, Ellen W.
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE; BACE inhibitors; Binding Sites; Biological and medical sciences; Computer Simulation; Humans; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.03.097

Structural biology allowed the identification of 7 as a potent BACE inhibitor (IC 50 = 5 nM). We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer’s disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100× more potent than 1, such as 7 (5 nM K i).