Design and synthesis of rho kinase inhibitors (III)
Design and synthesis of rho kinase inhibitors (III)
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DOI：
10.1016/j.bmc.2006.10.028
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发表时间：
2007-01-15
影响因子：
3.5
通讯作者：
Iijima, Hiroshi
中科院分区：
文献类型：
--
作者：
Iwakubo, Masayuki;Takami, Atsuya;Iijima, Hiroshi
研究了带有异喹啉支架的 Rho 激酶抑制剂的构效关系。 N-(1-苄基-3-吡咯烷基)-N-(5-异喹啉基)胺类似物针对其对酶和趋化性的抑制效力进行了优化。通过离体试验进一步评估有效的类似物，其中将所选化合物口服给予大鼠，并在给药后3小时评估在大鼠血清中观察到的Rho激酶抑制效力。化合物23g在大鼠血清中表现出高水平的Rho激酶抑制活性，并且在使用微粒体细胞色素制剂的体外代谢测试中是稳定的。在无细胞激酶测定和细胞迁移测定中，23g的(R)-异构体比(S)-异构体表现出更高水平的抑制效力(IC50ENZ = 25 nM和IC50MCP = 1 mu M)。 (R)-异构体成功抑制细胞中MBS（肌球蛋白结合亚基）的磷酸化。 (c) 2006 年，爱思唯尔有限公司出版。
The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3 h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC50ENZ = 25 nM and IC50MCP = 1 mu M). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells. (c) 2006 Published by Elsevier Ltd.