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

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, and others. (2007) Selective Urokinase-Type Plasminogen Activator Inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines. Journal of Medicinal Chemistry, 50 (10). pp. 2341-51. ISSN 0022-2623. (doi:10.1021/jm061066t) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1021/jm061066t

Abstract

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 (Ki 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 microM). 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.

Item Type: Article
DOI/Identification number: 10.1021/jm061066t
Subjects: Q Science > QD Chemistry
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: David Brown
Date Deposited: 11 Jun 2013 13:31 UTC
Last Modified: 29 May 2019 10:17 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/34256 (The current URI for this page, for reference purposes)
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