设计并合成具有细胞活性的 BACE-1 抑制剂：P1'取代基的构效关系。
Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents.
机构信息
Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
出版信息
Bioorg Med Chem Lett. 2009 Nov 15;19(22):6386-91. doi: 10.1016/j.bmcl.2009.09.061. Epub 2009 Sep 19.
PMID:19811916
Abstract
Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.
摘要
利用结构导向设计，羟乙胺 BACE-1 抑制剂被优化为纳摩尔级的 Abeta 细胞抑制作用，对组织蛋白酶-D 具有选择性。X 射线晶体学揭示了对这项工作至关重要的 S1' 残基，最终得到了化合物 56 和 57，它们表现出了活性和选择性，但通透性差，P-糖蛋白外排率高。
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