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

7 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

Access to Document

10.1016/j.bmcl.2011.12.123

Cite this

@article{e19705248d8547ebb5ae4be40eb5445c,

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",

author = "Massey, {Archna P.} and Harley, {William R.} and Nagarekha Pasupuleti and Gorin, {Fredric A.} and Nantz, {Michael H}",

year = "2012",

month = apr,

day = "1",

doi = "10.1016/j.bmcl.2011.12.123",

language = "English (US)",

volume = "22",

pages = "2635--2639",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "7",

}

TY - JOUR

T1 - 2-Amidino analogs of glycine-amiloride conjugates

T2 - Inhibitors of urokinase-type plasminogen activator

AU - Massey, Archna P.

AU - Harley, William R.

AU - Pasupuleti, Nagarekha

AU - Gorin, Fredric A.

AU - Nantz, Michael H

PY - 2012/4/1

Y1 - 2012/4/1

N2 - 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.

AB - 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.

KW - Lactate dehydrogenase

KW - Plasminogen activator inhibitor protein-1

KW - Tissue plasminogen activator

KW - Urokinase-type plasminogen activator

KW - Urokinase-type plasminogen activator receptor

UR - http://www.scopus.com/inward/record.url?scp=84858700139&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858700139&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2011.12.123

DO - 10.1016/j.bmcl.2011.12.123

M3 - Article

C2 - 22366654

AN - SCOPUS:84858700139

VL - 22

SP - 2635

EP - 2639

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 7

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this