Discovery of pyrrolidine-based β-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding efficiency

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 1; pp. 240 - 244
• Main Authors: Stachel, Shawn J., Steele, Thomas G., Petrocchi, Alessia, Haugabook, Sharie J., McGaughey, Georgia, Katharine Holloway, M., Allison, Timothy, Munshi, Sanjeev, Zuck, Paul, Colussi, Dennis, Tugasheva, Katherine, Wolfe, Abigail, Graham, Samuel L., Vacca, Joseph P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-01-2012; Elsevier
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; BACE-1; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Conformational design; Crystallization; Crystallography, X-Ray - methods; Drug Design; Enzyme Inhibitors - pharmacology; Inhibitor; Inhibitory Concentration 50; Ligand binding efficiency; Ligands; Medical sciences; Models, Chemical; molecular conformation; Pharmacology. Drug treatments; physical properties; Protein Binding; proteinase inhibitors; Pyrrolidine; pyrrolidines; Pyrrolidines - pharmacology; Rational design; Structure-Activity Relationship; Ligand binding efficiency; Inhibitor; Conformational design; Rational design; Pyrrolidine; BACE-1; Ligand binding; Efficiency; Enzyme inhibitor; Pyrrolidine derivatives; Conformation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.11.024

We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion and allowed for potent binding in a nontraditional fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.
We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.