Development of specific Rho-kinase inhibitors and their clinical application
Development of specific Rho-kinase inhibitors and their clinical application
复制标题
DOI：
10.1016/j.bbapap.2005.06.015
复制
发表时间：
2005-12-30
影响因子：
3.2
通讯作者：
Hidaka, H
中科院分区：
文献类型：
--
作者：
Tamura, M;Nakao, H;Hidaka, H
六氢-1-（异喹啉-5-磺酰基）- ih -1,4-二氮卓，HA-1077，是一种已知的rho激酶选择性抑制剂。虽然其对rho激酶的IC50值比对PKA、PKB、PKC、PKG、MLCK、CaMKII等激酶的IC50值低10倍以上，但对这些激酶仍具有较强的抑制活性。为了生产高特异性的rho激酶抑制剂，合成了几种HA-1077类似物并评估了它们的激酶抑制性能。(S)-六氢-1-（4-乙烯基喹啉-5-磺酰基）-2-甲基- ih -1,4-二氮平被发现是一种有效的rho激酶抑制剂。对rho激酶的IC50值为6 nM，对其他激酶的IC50值与HA-1077基本相同。基于PKA和HA-1077的复杂结构，设计了HA-1077类似物。其中，(S)-六氢-4-甘酰基-2-甲基-1-（4-甲基异喹啉-5-磺酰基）- 1h -1,4-二氮平和其他甘氨酸衍生物被发现是高度特异性的rho激酶抑制剂。这些rho激酶特异性抑制剂应用于兔眼高血压模型，显示出降低眼压的作用。这些结果表明，新的5-异喹啉磺酰酰胺不仅是有效的ROCK选择性化合物，而且在临床应用中也是有用的化合物。(c) 2005 Elsevier B.V.版权所有
Hexahydro-1-(isoquinoline-5-sulfonyl)-IH-1,4-diazepine, HA-1077, is a known selective inhibitor of Rho-kinase. Although its IC50 value against Rho-kinase is more than 10 times lower than those for kinases such as PKA, PKB, PKC, PKG, MLCK, CaMKII and others, the molecule still retains relative potent inhibition activities against these kinases. In order to produce highly specific Rho-kinase inhibitors, several HA-1077 analogs were synthesized and their kinase inhibition properties evaluated. (S)-Hexahydro-1-(4-ethenytisoquinoline-5-sulfonyl)-2-methyl-IH-1,4-diazepine was found to be a potent Rho-kinase inhibitor. The IC50 value against Rho-kinase was 6 nM, while those against other kinases remained at almost the same level as that of HA-1077. Furthermore, we designed HA-1077 analogs on the basis of the complex structure of PKA and HA-1077. Amongst these, (S)-hexahydro-4-glycyl-2-methyl-1-(4-methylisoquinoline-5-sulfonyl)-1H-1,4-diazepine and other glycine derivatives were found to be highly specific Rho-kinase inhibitors. These Rho-kinase specific inhibitors were applied to rabbit ocular hypertensive models and were shown to reduce intraocular pressure. These results demonstrate that the new 5-isoquinolinesulfonylamides are not only potent ROCK selective compounds, but are also useful compounds for clinical applications. (c) 2005 Elsevier B.V. All rights reserved.