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Publication Abstract from PubMed

The aspartyl protease beta-secretase, or BACE1, 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 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.

Discovery and Optimization of a Novel Spiro-pyrrolidine Inhibitors of beta-Secretase (BACE1) Through Fragment Based Drug Design.,Efremov IV, Vajdos FF, Borzilleri K, Capetta S, Dorff PH, Dutra JK, Mansour M, Chen H, Goldstein SW, Noell S, Oborski CE, O'Connell TN, O'Sullivan TJ, Pandit J, Wang H, Wei B, Withka JM, McColl A J Med Chem. 2012 Apr 2. PMID:22468999^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.