Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

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• 作者：Jack D. Scott ; Sarah W. Li ; Andrew P. J. Brunskill ; Xia Chen ; Kathleen Cox ; Jared N. Cumming ; Mark Forman ; Eric J. Gilbert ; Robert A. Hodgson ; Lynn A. Hyde ; Qin Jiang ; Ulrich Iserloh ; Irina Kazakevich ; Reshma Kuvelkar ; Hong Mei ; John Meredith ; Jeffrey Misiaszek ; Peter Orth ; Lana M. Rossiter ; Meagan Slater ; Julie Stone ; Corey O. Strickland ; Johannes H. Voigt ; Ganfeng Wang ; Hongwu Wang ; Yusheng Wu ; William J. Greenlee ; Eric M. Parker ; Matthew E. Kennedy ; Andrew W. Stamford
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：59
• 期：23
• 页码：10435-10450
• 全文大小：726K
• ISSN：1520-4804

文摘

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer’s disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.