一种强效且口服有效的、基于羟乙胺的β-分泌酶抑制剂。
A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase.
作者信息
Kaller Matthew R, Harried Scott S, Albrecht Brian, Amarante Patricia, Babu-Khan Safura, Bartberger Michael D, Brown James, Brown Ryan, Chen Kui, Cheng Yuan, Citron Martin, Croghan Michael D, Graceffa Russell, Hickman Dean, Judd Ted, Kriemen Chuck, La Daniel, Li Vivian, Lopez Patricia, Luo Yi, Masse Craig, Monenschein Holger, Nguyen Thomas, Pennington Lewis D, Miguel Tisha San, Sickmier E Allen, Wahl Robert C, Weiss Matthew M, Wen Paul H, Williamson Toni, Wood Stephen, Xue May, Yang Bryant, Zhang Jianhua, Patel Vinod, Zhong Wenge, Hitchcock Stephen
机构信息
Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
出版信息
ACS Med Chem Lett. 2012 Mar 29;3(11):886-91. doi: 10.1021/ml3000148. eCollection 2012 Nov 8.
β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Aβ40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.
β-分泌酶抑制剂可能是用于治疗阿尔茨海默病的疾病修饰疗法。我们实验室之前的研究成果产生了羟乙胺衍生的抑制剂，如对β-淀粉样前体蛋白裂解酶（BACE）具有低纳摩尔效力的化合物1。静脉给药时，化合物1也被证明能显著降低血浆、大脑和脑脊液中的Aβ40水平。在此，我们报告了进一步的优化，从而发现了抑制剂16，它是一种新型、高效且口服有效的BACE抑制剂。
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