title: H-series protein kinase inhibitors and potential clinical applications.
abstract: During the course of generating derivatives of N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide, a synthetic calmodulin inhibitor, we came across several analogues with shorter alkyl chains that exhibited inhibition of serine/threonine protein kinase activities in an ATP-competitive manner. Certain derivatives proved to be selective inhibitors of protein kinases useful for elucidation of relevant functions of the enzymes. One of them turned out to be a unique vasodilator that preferentially suppresses delayed cerebral vasospasm, a critical complication of subarachnoid hemorrhage, without significant changes in systemic blood pressure. The compound in question, 1-(5-isoquinolinesulfonyl)-homopiperazine, was identified from sequential development of protein kinase inhibitors with isoquinolinesulfonyl structures, which occupy the adenine pocket of the ATP-binding site of the enzyme. It recently has been proposed that the target kinase responsible for vasodilation by 1-(5-isoquinolinesulfonyl)-homopiperazine may be Rho-kinase, which regulates phosphorylation of myosin light chains and vasocontraction. Because protein phosphorylation plays important roles in regulation of various cellular functions, the foregoing is a good example of current progress in the development of protein kinase inhibitors with potential clinical applications.
authors.affiliation: Department of Pharmacology, Nagoya University School of Medicine, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ono-Saito
authors.forename: I
authors.initials: I
authors.lastname: Niki
authors.forename: H
authors.initials: H
authors.lastname: Hidaka
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005544:Forecasting; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011506:Proteins / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011506:Proteins; D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil