Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS A尾 Reduction

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• 作者：Andrew W. Stamford ; Jack D. Scott ; Sarah W. Li ; Suresh Babu ; Dawit Tadesse ; Rachael Hunter ; Yusheng Wu ; Jeffrey Misiaszek ; Jared N. Cumming ; Eric J. Gilbert ; Chunli Huang ; Brian A. McKittrick ; Liwu Hong ; Tao Guo ; Zhaoning Zhu ; Corey Strickland ; Peter Orth ; Johannes H. Voigt ; Matthew E. Kennedy ; Xia Chen ; Reshma Kuvelkar ; Robert Hodgson ; Lynn A. Hyde ; Kathleen Cox ; Leonard Favreau ; Eric M. Parker ; William J. Greenlee
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：3
• 期：11
• 页码：897-902
• 全文大小：319K
• 年卷期：v.3,no.11(November 8, 2012)
• ISSN：1948-5875

文摘

Inhibition of BACE1 to prevent brain A尾 peptide formation is a potential disease-modifying approach to the treatment of Alzheimer鈥檚 disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS A尾 levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF A尾40 levels when administered orally to rats.

Keywords:

BACE1; inhibitor; Alzheimer鈥檚 disease; A尾40; iminopyrimidinone; X-ray crystallography