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

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• 作者：Heinrich Rueeger ; Rainer Lueoend ; Olivier Rogel ; Jean-Michel Rondeau ; Henrik M枚bitz ; Rainer Machauer ; Laura Jacobson ; Matthias Staufenbiel ; Sandrine Desrayaud ; Ulf Neumann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3364-3386
• 全文大小：968K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

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 structure鈥揳ctivity relationship development were 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 the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood鈥揵rain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC₅₀ values 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 渭mol/kg demonstrated significant reduction of brain A尾 levels.