title: Design, synthesis and evaluation of biological activity of novel fasudil analogues.
abstract: Nine isoquinoline Rho kinase inhibitors were designed and synthesized on the basis of a ligand-binding pocket model. With fasudil, the only Rho kinase inhibitor marketed to date, as a reference compound, their biological activities were determined, including assays of Rho kinase inhibitory activity, synapse formation, cell viability. Bio-assays were performed by means of MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assays and lactate dehydrogenase (LDH) assays. The obtained results indicated that (R)-6H-1-(5-isoquinolinesulfonyl)-2-hydroxy methyl-1-pyrrolidine and (R)-6H-1-(5-isoquinolinesulfonyl)-2-chloromethyl-1-pyrrolidine exhibited excellent Rho kinase inhibitory activity, deactivation of Rho kinase led to accelerated synapse formation and enhanced cell viability. Therefore they might be potential candidates for preventing various neurological disorders. The brief study on the structure-activity relationship of these isoquinoline analogues demonstrated that modification of inhibitors targeting region D of the Rho kinase binding pocket is quite efficacious, the existence of free amino, chloro- or hydroxyl group as binding sites with region D of Rho kinase is necessary for increasing the inhibitory activity.
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.forename: Donghua
authors.initials: D
authors.lastname: Wang
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.forename: Changhai
authors.initials: C
authors.lastname: Sun
authors.forename: Meizhu
authors.initials: M
authors.lastname: Chen
authors.forename: Xinran
authors.initials: X
authors.lastname: Wang
authors.forename: Ligong
authors.initials: L
authors.lastname: Chen
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017628:Microglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D007770:L-Lactate Dehydrogenase; D054460:rho-Associated Kinases; C049347:fasudil