National Center for
3UDM: Crystal Structure of BACE with Compound 8
Discovery and optimization of a novel spiropyrrolidine inhibitor of beta-secretase (BACE1) through fragment-based drug design
J. Med. Chem. (2012) 55 p.9069-9088» All references (2)
The aspartyl protease beta-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Abeta-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.