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

…, A Petrocchi, SJ Haugabook, G McGaughey…

文献索引：Stachel, Shawn J.; Steele, Thomas G.; Petrocchi, Alessia; Haugabook, Sharie J.; McGaughey, Georgia; Katharine Holloway; Allison, Timothy; Munshi, Sanjeev; Zuck, Paul; Colussi, Dennis; Tugasheva, Katherine; Wolfe, Abigail; Graham, Samuel L.; Vacca, Joseph P. Bioorganic and Medicinal Chemistry Letters, 2012 , vol. 22, # 1 p. 240 - 244

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被引用次数: 20

摘要

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 ...