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

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 4; pp. 1557 - 1568
• Main Authors: Venkatraj, Muthusamy, Messagie, Jonas, Joossens, Jurgen, Lambeir, Anne-Marie, Haemers, Achiel, Van der Veken, Pieter, Augustyns, Koen
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2012; Elsevier
• 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; Naphthalene sulfonamides; Naphthamides; tPA; Urokinase inhibitors; uPA; Evaluation; u-Plasminogen activator; Sulfonamide; Serine endopeptidases; Enzyme; Chemical structure; Naphthalene derivatives; t-Plasminogen activator; Peptidases; Naphthalene; Sulfonamides; Hydrolases; Carboxamide; Inhibitor; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.12.040

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.