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