title: Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA).
abstract: A known side-activity of the oral potassium-sparing diuretic drug amiloride is inhibition of the enzyme urokinase-type plasminogen activator (uPA, K(i)=7 μM), a promising anticancer target. Several studies have demonstrated significant antitumor/metastasis properties for amiloride in animal cancer models and it would appear that these arise, at least in part, through inhibition of uPA. Selective optimization of amiloride's structure for more potent inhibition of uPA and loss of diuretic effects would thus appear as an attractive strategy towards novel anticancer agents. The following report is a preliminary structure-activity exploration of amiloride analogs as inhibitors of uPA. A key finding was that the well-studied 5-substituted analogs ethylisopropyl amiloride (EIPA) and hexamethylene amiloride (HMA) are approximately twofold more potent than amiloride as uPA inhibitors.
authors: School of Chemistry, University of Wollongong, NSW 2522, Australia.
authors: Hayden
authors: H
authors: Matthews
authors: Marie
authors: M
authors: Ranson
authors: Joel D A
authors: JD
authors: Tyndall
authors: Michael J
authors: MJ
authors: Kelso
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004232:Diuretics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004232:Diuretics; D000584:Amiloride; D014568:Urokinase-Type Plasminogen Activator