H-series protein kinase inhibitors and potential clinical applications.

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.