Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P₂ position

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• 作者：Yoshio Hamada ; Tomoya Nakanishi ; Kenji Suzuki ; Ryoji Yamaguchi ; Takashi Hamada ; Koushi Hidaka ; Shoichi Ishiura ; Yoshiaki Kiso
• 关键词：Alzheimer&rsquo ; s disease ; ¦Â-Secretase ; BACE1 ; BACE1 inhibitor
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：15 July, 2012
• 年：2012
• 卷：22
• 期：14
• 页码：4640-4644
• 全文大小：1185 K

文摘

Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P₂ position. By studying the structure-activity relationship of these inhibitors, we found that the ¦Ò-¦Ð interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P₂ regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P₂ position are described along with the results of the related structure-activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability.