Download MendeleyDiscovery of pyrrolidine-based beta-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding efficiency.
Stachel, S.J., Steele, T.G., Petrocchi, A., Haugabook, S.J., McGaughey, G., Katharine Holloway, M., Allison, T., Munshi, S., Zuck, P., Colussi, D., Tugasheva, K., Wolfe, A., Graham, S.L., Vacca, J.P.(2012) Bioorg Med Chem Lett 22: 240-244
- PubMed: 22130130
- DOI: https://doi.org/10.1016/j.bmcl.2011.11.024
- Primary Citation of Related Structures:
3UFL - PubMed Abstract:
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.
Organizational Affiliation:
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. [email protected]
