Shimamoto Yasuhiro, Hattori Yasunao, Kobayashi Kazuya, Teruya Kenta, Sanjoh Akira, Nakagawa Atsushi, Yamashita Eiki, Akaji Kenichi
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto 606-0823, Japan.
Bioorg Med Chem. 2015 Feb 15;23(4):876-90. doi: 10.1016/j.bmc.2014.12.028. Epub 2014 Dec 20.
The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro)) are described. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P2 position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CL(pro), which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CL(pro) inhibitor. X-ray crystallographic analyses of the SARS 3CL(pro) in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.
本文描述了一种新型十氢异喹啉支架作为严重急性呼吸综合征（SARS）类胰凝乳蛋白酶样蛋白酶（3CL(pro)）抑制剂的设计与评估。通过关注S2位点的疏水相互作用，十氢异喹啉支架的设计是将基于底物的抑制剂的P2位点环己基通过亚甲基连接基连接到P2位置α-氮原子处的主链上。从通过盐析拆分得到的环己烯对映体出发，合成了反式十氢异喹啉衍生物。所有合成的十氢异喹啉抑制剂对SARS 3CL(pro)均表现出中等但明确的抑制活性，这证实了十氢异喹啉的稠环结构可作为SARS 3CL(pro)抑制剂的新型支架。SARS 3CL(pro)与十氢异喹啉抑制剂复合物的X射线晶体学分析揭示了在S1和S2位点的预期相互作用，以及抑制剂N-取代基处的额外相互作用。
