Selective Urokinase-Type Plasminogen Activator Inhibitors. 4. 1-(7-Sulfonamidoisoquinolinyl)guanidines

• Published in: Journal of medicinal chemistry Vol. 50; no. 10; pp. 2341 - 2351
• Main Authors: Fish, Paul V, Barber, Christopher G, Brown, David G, Butt, Richard, Collis, Michael G, Dickinson, Roger P, Henry, Brian T, Horne, Valerie A, Huggins, John P, King, Elizabeth, O'Gara, Margaret, McCleverty, Dawn, McIntosh, Fraser, Phillips, Christopher, Webster, Robert
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 17-05-2007
• Subjects: Acute Disease; Animals; Anti-Ulcer Agents - chemical synthesis; Anti-Ulcer Agents - chemistry; Anti-Ulcer Agents - pharmacology; Binding Sites; Biological and medical sciences; Chronic Disease; Crystallography, X-Ray; Guanidines - chemical synthesis; Guanidines - chemistry; Guanidines - pharmacology; Humans; In Vitro Techniques; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Skin - injuries; Skin Diseases - enzymology; Skin, nail, hair, dermoskeleton; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Swine; Ulcer - enzymology; Urokinase-Type Plasminogen Activator - antagonists & inhibitors; Urokinase-Type Plasminogen Activator - chemistry; Wound Healing - drug effects; Skin disease; u-Plasminogen activator; Isoquinoline derivatives; Sulfonamide; Serine endopeptidases; Enzyme; Non peptide compound; Guanidines; Selectivity; In vitro; Wound; Pig; Peptidases; In vivo; Vertebrata; Mammalia; Treatment; Structure activity relation; Animal; Hydrolases; Ulcer; Inhibitor; Artiodactyla; Ungulata
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061066t

1-Isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (K i 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50 = 0.89 μM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.