Design and Synthesis of 尾-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of 尾-Amyloid Peptides

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• 作者：Britt-Marie Swahn ; Karin Kolmodin ; Sofia Karlstr枚m ; Stefan von Berg ; Peter S枚derman ; J枚rg Holenz ; Stefan Berg ; Johan Lindstr枚m ; Marie Sundstr枚m ; Dominika Turek ; Jacob Kihlstr枚m ; Can Slivo ; Lars Andersson ; David Pyring ; Didier Rotticci ; Liselotte 脰hberg ; Annika Kers ; Krisztian Bogar ; Fredrik von Kieseritzky ; Margareta Bergh ; Lise-Lotte Olsson ; Juliette Janson ; Susanna Eketj盲ll ; Biljana Georgievska ; Fredrik Jeppsson ; Johanna F盲lting
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9346-9361
• 全文大小：551K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

The evaluation of a series of aminoisoindoles as 尾-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer鈥檚 disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of A尾40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC₅₀ values of 8.6 and 0.16 nM, respectively, and hERG IC₅₀ values of 16 and 2.8 渭M, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of 尾-amyloid peptides in mouse brain following oral dosing.