Novel BACE1 inhibitors with a non-acidic heterocycle at the P₁¡ä position

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• 作者：Kenji Suzuki ; Yoshio Hamada ; Jeffrey-Tri Nguyen ; Yoshiaki Kiso
• 关键词：Non-acidic inhibitor ; ¦Â-Secretase ; Alzheimer&rsquo ; s disease ; Quantitative structure&ndash ; activity relationship ; Hydroxymethylcarbonyl isostere
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 November, 2013
• 年：2013
• 卷：21
• 期：21
• 页码：6665-6673
• 全文大小：1573 K

文摘

We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P₁¡ä position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P₁¡ä position. KMI-1764 (27) exhibited potent inhibitory activity (IC₅₀ = 27 nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure-activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model.