Study Of Rho Kinase Inhibitors With Isoquinoline Scaffold And 4-pyridine Scaffold

Multiple sclerosis is a chronic autoimmune disease characterized by the white matter of the central nervous system(CNS)and the infiltration of inflammatory cellsStudies show that Rho kinase has a variety of drug targets Abnormal activation of Rho/Rock has been observed in various disorders of the CNS Furthermore,the dysregulation of ROCK activity is important in the pathogenesis of many neurological diseases,inhibition of Rho kinase can regulate immune,anti-inflammatory,promoting neurite outgrowth and neural stem cell proliferation differentiation and restore the function of damaged nerve As the only listed Rho kinase inhibitor,Fasudil has a definite therapeutic effect on MS Therefore,we take Rho kinase as the target,designed and synthesized a series of Rho kinase inhibitors with isoquinoline scaffold for the treatment of MS Compared with fasudil,Y-27632 represent stronger inhibition activity to Rho kinase In addition,Dalfampridine,ie 4-aminopyridine,is a potassium channel blocker of broad spectrum,has been found to improve walking in patients with any type of MS However,there are many adverse reactions in clinical trials Therefore,we hope to design and synthesize some Rho kinase inhibitors with 4-aminopyridine scaffold which can significantly improve the walking ability of MS patients and the adverse reactions are less1: Seven ROCK inhibitors were designed and synthezed with Fasudil as the lead compound based on ligand-binding pocket model The compounds were tested for EAE activity in vivo But none of them can relieve clinical symptoms of EAE effectively2 Established routes for the synthesis of Rho kinase inhibitor with 4-aminopyridine scaffold Six compounds were designed and synthesized with 4 aminopyridine as the lead compound,by nucleophilic substitution,by modification of the primary amine in 4-aminopyridine obtained target products At present,the inhibitory effect of 6 compounds on hERG at different concentrations was tested,and it was found that compound 9 had better inhibitory effect on hERG...