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Structure-based design and synthesis of novel P2/P3 modified, non-peptidic β-secretase (BACE-1) inhibitors

Hanessian, Stephen and Shao, Zhihui and Betschart, Claudia and Rondeau, Jean-Michel and Neumann, Ulf and Tintelnot-Blomley, Marina (2010) Structure-based design and synthesis of novel P2/P3 modified, non-peptidic β-secretase (BACE-1) inhibitors. Bioorganic and Medicinal Chemistry Letters, 20 (6). pp. 1924-1927. ISSN 0960-894X

Abstract

Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D. © 2010 Elsevier Ltd. All rights reserved.

Item Type: Article
Keywords: Alzheimer's disease Peptidomimetic Protease inhibitor
Date Deposited: 01 Dec 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/1970

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