β-分泌酶抑制剂：P4位修饰及在培养细胞中抑制活性的提高
beta-Secretase inhibitors: modification at the P4 position and improvement of inhibitory activity in cultured cells.
作者信息
Hamada Yoshio, Igawa Naoto, Ikari Hayato, Ziora Zyta, Nguyen Jeffrey-Tri, Yamani Abdellah, Hidaka Koushi, Kimura Tooru, Saito Kazuki, Hayashi Yoshio, Ebina Maiko, Ishiura Shoichi, Kiso Yoshiaki
机构信息
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Japan.
出版信息
Bioorg Med Chem Lett. 2006 Aug 15;16(16):4354-9. doi: 10.1016/j.bmcl.2006.05.046. Epub 2006 Jun 6.
Recently, we reported potent and small-sized beta-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.
最近，我们报道了强效且小分子的β-分泌酶（BACE1）抑制剂KMI-570和KMI-684，在这两种抑制剂中，我们分别用四唑衍生物作为羧酸生物电子等排体，取代了KMI-420和KMI-429的P(1)′位的羧酸基团。这些修饰显著提高了BACE1抑制活性和化学稳定性。在本研究中，分别将KMI-420和KMI-570的P(4)位的酸性四唑环替换为各种氢键受体基团。我们发现BACE1抑制剂KMI-574在培养细胞以及体外酶活性测定中均表现出强效抑制活性。
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