Novel pyrrolyl 2-aminopyridines as potent and selective human β-secretase (BACE1) inhibitors

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• 作者：Michael S. Malamas ; Keith Barnes ; Yu Hui ; Matthew Johnson ; Frank Lovering ; Jeff Condon ; William Fobare ; William Solvibile ; Jim Turner ; Yun Hu ; Eric S. Manas ; Kristi Fan ; Andrea Oll ; Rajiv Chopra ; Jon
• 关键词：Alzheimer’ ; s disease (AD) ; BACE1 inhibitors ; Beta-amyloid peptide (Aβ ; ) ; 2-Aminopyridines
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 April 2010
• 年：2010
• 卷：20
• 期：7
• 页码：2068-2073
• 全文大小：531 K

文摘

The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer’s disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood–brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.