2-Amidino analogs of glycine-amiloride conjugates: Inhibitors of urokinase-type plasminogen activator

Archna P. Massey; William R. Harley; Nagarekha Pasupuleti; Fredric A. Gorin; Michael H Nantz

doi:10.1016/j.bmcl.2011.12.123

2-Amidino analogs of glycine-amiloride conjugates: Inhibitors of urokinase-type plasminogen activator

Archna P. Massey, William R. Harley, Nagarekha Pasupuleti, Fredric A. Gorin, Michael H Nantz

Neurology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

The relative non-toxicity of the diuretic amiloride, coupled with its selective inhibition of the protease urokinase plasminogen activator (uPA), makes this compound class attractive for structure-activity studies. Herein we substituted the C(2)-acylguanidine of C(5)-glycyl-amiloride with amidine and amidoxime groups. The data show the importance of maintaining C(5)-hydrophobicity. The C(5)-benzylglycine analogs containing either C(2)-acylguanidine or amidine inhibited uPA with an IC ₅₀ ranging from 3 to 7 μM and were cytotoxic to human U87 malignant glioma cells.

Original language	English (US)
Pages (from-to)	2635-2639
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	7
DOIs	https://doi.org/10.1016/j.bmcl.2011.12.123
State	Published - Apr 1 2012

Keywords

Lactate dehydrogenase
Plasminogen activator inhibitor protein-1
Tissue plasminogen activator
Urokinase-type plasminogen activator
Urokinase-type plasminogen activator receptor

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery
Organic Chemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry
Biochemistry

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title = "2-Amidino analogs of glycine-amiloride conjugates: Inhibitors of urokinase-type plasminogen activator",

abstract = "The relative non-toxicity of the diuretic amiloride, coupled with its selective inhibition of the protease urokinase plasminogen activator (uPA), makes this compound class attractive for structure-activity studies. Herein we substituted the C(2)-acylguanidine of C(5)-glycyl-amiloride with amidine and amidoxime groups. The data show the importance of maintaining C(5)-hydrophobicity. The C(5)-benzylglycine analogs containing either C(2)-acylguanidine or amidine inhibited uPA with an IC 50 ranging from 3 to 7 μM and were cytotoxic to human U87 malignant glioma cells.",

keywords = "Lactate dehydrogenase, Plasminogen activator inhibitor protein-1, Tissue plasminogen activator, Urokinase-type plasminogen activator, Urokinase-type plasminogen activator receptor",

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AU - Harley, William R.

AU - Pasupuleti, Nagarekha

AU - Gorin, Fredric A.

AU - Nantz, Michael H

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KW - Plasminogen activator inhibitor protein-1

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KW - Urokinase-type plasminogen activator receptor

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