Structure-activity relationship study of BACE1 inhibitors possessing a chelidonic or 2,6-pyridinedicarboxylic scaffold at the P2 position
Structure-activity relationship study of BACE1 inhibitors possessing a chelidonic or 2,6-pyridinedicarboxylic scaffold at the P2 position
复制标题
P2位点具有白屈菜或2,6-吡啶二羧酸支架的BACE1抑制剂的构效关系研究
DOI：
10.1016/j.bmcl.2013.12.007
复制
发表时间：
2014
影响因子：
2.7
通讯作者：
Yoshiaki Kiso
中科院分区：
文献类型：
--
作者：
Yoshio Hamada;Kenji Suzuki;Tomoya Nakanishi;Diganta Sarma;Hiroko Ohta;Ryoji Yamaguchi;Moe Yamasaki;Koushi Hidaka;Shoichi Ishiura;Yoshiaki Kiso
我们之前已经报道了基于底物的有效五肽BACE 1抑制剂，其具有羟甲基羰基电子等排体作为底物过渡态模拟物。虽然这些抑制剂在酶和细胞试验中表现出有效的活性（KMI-429特别抑制体内Aβ产生），但这些抑制剂含有一些天然氨基酸，这些氨基酸似乎是改善体内酶稳定性和穿过血脑屏障的渗透性所必需的，因此是实用的药物。最近，我们合成了在P2位具有杂环骨架的非肽和小尺寸的BACE 1抑制剂。在这里，我们报告的SAR研究BACE 1抑制剂具有这种杂环支架，一个chelidonic或2，6-pyridinedicarboxylic部分。
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 P2position. Herein we report the SAR study of BACE1 inhibitors possessing this heterocyclic scaffold, a chelidonic or 2,6-pyridinedicarboxylic moiety.