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Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA)

Journal Article


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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. © 2011 Elsevier Ltd. All rights reserved.

Publication Date


  • 2011

Citation


  • Matthews, H., Ranson, M., Tyndall, J. D. A. & Kelso, M. J. (2011). Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA). Bioorganic and Medicinal Chemistry Letters, 21 (22), 6760-6766.

Scopus Eid


  • 2-s2.0-80054744515

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=7237&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/3895

Has Global Citation Frequency


Number Of Pages


  • 6

Start Page


  • 6760

End Page


  • 6766

Volume


  • 21

Issue


  • 22

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. © 2011 Elsevier Ltd. All rights reserved.

Publication Date


  • 2011

Citation


  • Matthews, H., Ranson, M., Tyndall, J. D. A. & Kelso, M. J. (2011). Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA). Bioorganic and Medicinal Chemistry Letters, 21 (22), 6760-6766.

Scopus Eid


  • 2-s2.0-80054744515

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=7237&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/3895

Has Global Citation Frequency


Number Of Pages


  • 6

Start Page


  • 6760

End Page


  • 6766

Volume


  • 21

Issue


  • 22