Synthesis and evaluation of non-basic inhibitors of urokinase-type plasminogen activator (uPA)

A series of non-basic naphthamides and naphthalene sulfonamides were synthesized and evaluated for uPA inhibition. Several non-basic compounds showed comparable uPA inhibition and selectivity with reference amidines. Recent drug discovery programs targeting urokinase plasminogen activator (uPA) have...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2012-02, Vol.20 (4), p.1557-1568
Main Authors: Venkatraj, Muthusamy, Messagie, Jonas, Joossens, Jurgen, Lambeir, Anne-Marie, Haemers, Achiel, Van der Veken, Pieter, Augustyns, Koen
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Binding, Competitive
bioavailability
Biological and medical sciences
Biological Availability
chemistry
drugs
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Hydrogen-Ion Concentration
Inhibitory Concentration 50
Medical sciences
Molecular Structure
naphthalene
Naphthalene sulfonamides
Naphthalenes - chemical synthesis
Naphthalenes - chemistry
Naphthalenes - pharmacology
Naphthamides
Pharmacology. Drug treatments
Protein Binding - drug effects
sulfonamides
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
tPA
u-plasminogen activator
uPA
Urokinase inhibitors
Urokinase-Type Plasminogen Activator - antagonists & inhibitors
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Summary:A series of non-basic naphthamides and naphthalene sulfonamides were synthesized and evaluated for uPA inhibition. Several non-basic compounds showed comparable uPA inhibition and selectivity with reference amidines. Recent drug discovery programs targeting urokinase plasminogen activator (uPA) have resulted in nonpeptidic inhibitors consisting of amidine or guanidine functional groups attached to aromatic or heteroaromatic scaffolds. There is a general problem of poor oral bioavailability of these charged inhibitors. In this paper, we report the synthesis and evaluation of a series of naphthamide and naphthalene sulfonamides as uPA inhibitors containing non-basic groups as substitute for amidine or guanidine groups.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.12.040