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Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure Based Design and In Vivo Reduction of Amyloid β-Peptides

Rueeger, Heinrich and Lueoend, Rainer Martin and Rogel, Olivier and Rondeau, Jean-Michel and Moebitz, Henrik and Machauer, Rainer and Jacobson, Laura and Staufenbiel, Matthias and Desrayaud, Sandrine and Neumann, Ulf (2012) Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure Based Design and In Vivo Reduction of Amyloid β-Peptides. Journal of Medicinal Chemistry, 55 (7). pp. 3364-3386. ISSN 0022-2623

Abstract

Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the SAR development was supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed to enhance potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with CNS drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure based optimization we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 of 2 and 50 nM, respectively and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 µmol/kg demonstrated significant reduction of brain Aβ levels.

Item Type: Article
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Keywords: BACE1, beta-site APP-cleaving enzyme, β-Secretase, Hydroxyethylamine BACE1 inhibitors, Structure based design, Alzheimer’s disease, blood-brain barrier permeability
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6447

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