Acylguanidine inhibitors of β-secretase: Optimization of the pyrrole ring substituents extending into the S₁ and S₃ substrate binding pockets

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• 作者：Derek C. Cole ; Joseph R. Stock ; Rajiv Chopra ; Rebecca Cowling ; John W. Ellingboe ; Kristi Y. Fan ; Boyd L. Harrison ; Yun Hu ; Steve Jacobsen ; Lee D. Jennings ; Guixian Jin ; Peter A. Lohse ; Michael S. Mala
• 关键词：BACE-1 ; β ; -Secretase ; Inhibitor ; Acylguanidine
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：1 February 2008
• 年：2008
• 卷：18
• 期：3
• 页码：1063-1066
• 全文大小：406 K

文摘

Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE-1) and γ-secretase leads to formation of β-amyloid (Aβ) a key component of amyloid plaques, which are considered the hallmark of Alzheimer’s disease. Small molecule inhibitors of BACE-1 may reduce levels of Aβ and thus have therapeutic potential for treating Alzheimer’s disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S₁ and S_2′ pockets leading to submicromolar BACE-1 inhibitors.