Study Of Rho Kinase Inhibitors With Isoquinoline Scaffold And4-pyridine Scaffold

Rho kinase (ROCK) is a new important target implicated in neural andcardiovascular disorders. However, the activated kinases can lead to hypertension,coronary heart disease (CDH), cerebral ischemia or other diseases. As a typical andthe only marketed Rho kinase inhibitor, Fasudil can effectively alleviate the cerebralvasospasm and improve subarachnoid hemorrhage (SAH) prognosis of patients.Furthermore, Fasudil has a huge potential for preventing other diseases. Thus it is anew drug with a wide range of pharmacological effects. Comparing with Fasudil,Y-27632exhibits better significant inhibition activity and it helps to fight againstalzheimer’s disease with intraperitoneal injection. Therefore, a series of ROCKinhibitors have been designed, synthesized and tested, according the structure ofFasudil and Y-27632.1. Nine ROCK inhibitors were designed and synthezed with Fasudil and Y-27632as the lead compound based on ligand-binding pocket model. The mice BV-2microglia cells and the primary neurons were employed in the biological experiment.The vitro biological activitity results show that compounds1and4exhibit bettersignificant inhibition activity of Rho kinases than other compounds. But due to poorlywater-soluble, they present no effective clinical results in vivo. However, compound8can relieve clinical symptoms of EAE effectively. Therefore, it is believed to be apotential candidate to be a drug.2. The synthetic route of Y-27632analogues was estiblished. It was obtainedfrom4-aminopyridine and ethyl chloroformate to synthesize the intermediate vianucleophilic substitution. Treatment of the intermediate with corresponding amines in1,4-dioxane with N-methylpyrrolidine as catalyst yielded the target products.