β-Secretase inhibitors:: Modification at the P4 position and improvement of inhibitory activity in cultured cells
β-Secretase inhibitors:: Modification at the P4 position and improvement of inhibitory activity in cultured cells
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DOI：
10.1016/j.bmcl.2006.05.046
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发表时间：
2006-08-15
影响因子：
2.7
通讯作者：
Kiso, Yoshiaki
中科院分区：
文献类型：
--
作者：
Hamada, Yoshio;Igawa, Naoto;Kiso, Yoshiaki
最近，我们报道了有效的和小尺寸的P-分泌酶（BACE 1）抑制剂KMI-570和KMI-684，其中我们分别用四唑衍生物作为羧酸生物电子等排体取代KMI-420和KMI-429的P-1（'）位的羧酸基团。这些修饰显著提高了BACE 1抑制活性和化学稳定性。在本研究中，KMI-420和KMI-570的P-4位的酸性四唑环分别被各种氢键受体基团取代。我们发现BACE 1抑制剂KMI-574在培养的细胞中以及在体外酶测定中表现出有效的抑制活性。(c)2006爱思唯尔有限公司保留所有权利。
Recently, we reported potent and small-sized P-secretase (BACE1) inhibitors KMI-570 and KMI-684 in which we replaced carboxylic acid groups at the P-1(') position of KMI-420 and KMI-429, respectively, with tetrazole derivatives as carboxylic acid bioisosteres. These modifications improved significantly BACE1 inhibitory activity and chemical stability. In this study, the acidic tetrazole ring of the P-4 position of KMI-420 and KMI-570, respectively, was replaced with various hydrogen bond acceptor groups. We found BACE1 inhibitor KMI-574 that exhibited potent inhibitory activity in cultured cells as well as in vitro enzymatic assay. (c) 2006 Elsevier Ltd. All rights reserved.