Structure-Based Design of 尾-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer鈥檚 Disease

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• 作者：Jing Yuan ; Shankar Venkatraman ; Yajun Zheng ; Brian M. McKeever ; Lawrence W. Dillard ; Suresh B. Singh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4156-4180
• 全文大小：1545K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-尾 (A尾) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer鈥檚 disease and dementia. The A尾 hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer鈥檚 and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia. This review summarizes two distinct categories of inhibitors designed based on conformational states of 鈥渃losed鈥?and 鈥渙pen鈥?forms of the enzyme. In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM). This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure鈥揳ctivity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data.