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Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors

Rueeger, Heinrich and Rondeau, Jean-Michel and Mccarthy, Clive and Moebitz, Henrik and Tintelnot-Blomley, Marina and Neumann, Ulf and Desrayaud, Sandrine (2011) Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors. Bioorganic & Medicinal Chemistry Letters, 21 (7). pp. 1942-1947. ISSN 0960-894X

Abstract

This letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Alzheimer’s disease; BACE-1; Beta secretase inhibitor; Cyclcic hydroxyethylamine transition state mimetic
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4780

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