Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima, Chuo-ku, Kobe 650-8586, Japan; Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Bioorg Med Chem Lett. 2014 Jan 15;24(2):618-23. doi: 10.1016/j.bmcl.2013.12.007. Epub 2013 Dec 8.
We have previously reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. While these inhibitors exhibited potent activities in enzymatic and cellular assays (KMI-429 in particular inhibited Aβ production in vivo), these inhibitors contained some natural amino acids that seemed to be required to improve enzymatic stability in vivo and permeability across the blood-brain barrier, so as to be practical drug. Recently, we synthesized non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold at the P2 position. Herein we report the SAR study of BACE1 inhibitors possessing this heterocyclic scaffold, a chelidonic or 2,6-pyridinedicarboxylic moiety.
我们之前曾报道过具有羟甲基羰基等排体的强效基于底物的五肽 BACE1 抑制剂，可作为底物过渡态模拟物。这些抑制剂在酶和细胞测定中表现出很强的活性（特别是 KMI-429 可抑制体内 Aβ 的产生），但这些抑制剂含有一些天然氨基酸，这些氨基酸似乎对提高体内酶的稳定性和血脑屏障的通透性是必需的，以达到实际药物的效果。最近，我们合成了具有杂环骨架的非肽类和小尺寸的 BACE1 抑制剂，其 P2 位具有杂环骨架、螯合或 2,6-吡啶二甲酸部分。本文报告了具有这种杂环骨架、螯合或 2,6-吡啶二甲酸部分的 BACE1 抑制剂的 SAR 研究。
