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

The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-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 interventi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-11, Vol.55 (21), p.9069-9088
Main Authors: Efremov, Ivan V, Vajdos, Felix F, Borzilleri, Kris A, Capetta, Steven, Chen, Hou, Dorff, Peter H, Dutra, Jason K, Goldstein, Steven W, Mansour, Mahmoud, McColl, Alexander, Noell, Stephen, Oborski, Christine E, O’Connell, Thomas N, O’Sullivan, Theresa J, Pandit, Jayvardhan, Wang, Hong, Wei, BinQing, Withka, Jane M
Format: Article
Language:English
Subjects:
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Amyloid Precursor Protein Secretases - chemistry
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - chemistry
Crystallography, X-Ray
Drug Design
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Models, Molecular
Molecular Structure
Pyrrolidines - chemical synthesis
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Spiro Compounds - chemical synthesis
Spiro Compounds - chemistry
Spiro Compounds - pharmacology
Stereoisomerism
Structure-Activity Relationship
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Summary:The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm201715d