Development of specific Rho-kinase inhibitors and their clinical application

Biochim Biophys Acta. 2005 Dec 30;1754(1-2):245-52. doi: 10.1016/j.bbapap.2005.06.015. Epub 2005 Sep 12.


Hexahydro-1-(isoquinoline-5-sulfonyl)-1H-1,4-diazepine, HA-1077, is a known selective inhibitor of Rho-kinase. Although its IC(50) 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-ethenylisoquinoline-5-sulfonyl)-2-methyl-1H-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.

Publication types

  • Review

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / chemistry
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / metabolism
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
  • Animals
  • Drug Design*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Rabbits
  • rho-Associated Kinases


  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • fasudil