Discovery and Optimization of a Novel Spiropyrrolidine Inhibitor of 尾-Secretase (BACE1) through Fragment-Based Drug Design

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• 作者：Ivan V. Efremov ; Felix F. Vajdos ; Kris A. Borzilleri ; Steven Capetta ; Hou Chen ; Peter H. Dorff ; Jason K. Dutra ; Steven W. Goldstein ; Mahmoud Mansour ; Alexander McColl ; Stephen Noell ; Christine E. Oborski ; Thomas N. O鈥機onnell ; Theresa J. O鈥橲ullivan ; Jayvardhan Pandit ; Hong Wang ; BinQing Wei ; Jane M. Withka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9069-9088
• 全文大小：806K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

The aspartyl protease 尾-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of A尾-peptide, a major component of plaques in the brains of Alzheimer鈥檚 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鈥檚 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.