Design and synthesis of Rho kinase inhibitors (II)
Design and synthesis of Rho kinase inhibitors (II)
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DOI：
10.1016/j.bmc.2006.09.052
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发表时间：
2007-01-01
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
在以前的研究中，我们确定了几个结构无关的骨架的Rho激酶抑制剂使用药效团信息获得的结果的高通量筛选和结构信息从同源模型的Rho激酶。1H-吲唑是一种新型的Rho激酶抑制剂的骨架材料。本研究对1H-吲唑类似物进行了详细的构效关系研究。在这项研究中，我们发现，具有1H-吲唑支架的Rho激酶抑制剂的无细胞酶抑制潜力不一定与它们对培养细胞的趋化性的抑制潜力相关。连接子结构的选择被证明是1H-吲唑类似物抑制细胞趋化性的重要因素。对1H-吲唑抑制剂在体外抑制MCP-1诱导的单核细胞趋化性方面进行了优化。在无细胞酶测定和趋化性测定中的抑制潜力都得到改善。(c)2006爱思唯尔有限公司版权所有。
In a previous study, we identified several structurally unrelated scaffolds of the Rho kinase inhibitor using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. 1H-Indazole is one of the candidate scaffolds on which a new series of potent Rho kinase inhibitors could be developed. In this study, the detailed structure-activity relationship of 1H-indazole analogues was studied. During this study, we found that the cell-free enzyme inhibitory potential of Rho kinase inhibitors having the 1H-indazole scaffold did not necessarily correlate with their inhibitory potential toward the chemotaxis of cultured cells. The choice of the linker substructure was shown to be an important factor for the 1H-indazole analogues to inhibit the chemotaxis of cells. Optimization of the 1H-indazole inhibitors with respect to the in vitro inhibition of monocyte chemotaxis induced by MCP-1 was carried out. The inhibitory potential was improved both in the cell-free enzyme assay and in the chemotaxis assay. (c) 2006 Elsevier Ltd. All rights reserved.