Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors
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Rueeger, Heinrich, Rondeau, Jean-Michel, Mccarthy, Clive, Moebitz, Henrik, Tintelnot-Blomley, Marina, 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 |