New Aminoimidazoles as 尾-Secretase (BACE-1) Inhibitors Showing Amyloid-尾 (A尾) Lowering in Brain

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• 作者：Ylva Gravenfors ; Jenny Viklund ; Jan Blid ; Tobias Ginman ; Sofia Karlstr枚m ; Jacob Kihlstr枚m ; Karin Kolmodin ; Johan Lindstr枚m ; Stefan von Berg ; Fredrik von Kieseritzky ; Can Slivo ; Britt-Marie Swahn ; Lise-Lotte Olsson ; Patrik Johansson ; Susanna Eketj盲ll ; Johanna F盲lting ; Fredrik Jeppsson ; Kia Str枚mberg ; Juliette Janson ; Fredrik Rahm
• 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：9297-9311
• 全文大小：470K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer鈥檚 disease. Synthetic methods, crystal structures, and structure鈥揳ctivity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in A尾40 and A尾42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain A尾 was 40鈥?0%, 1.5 h after oral dosing (100 渭mol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.