- Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-Sulfonamidoisoquinolinyl)guanidines
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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 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.
- 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
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p. 2341 - 2351
(2008/02/03)
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- Composition for the treatment of damaged tissue
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A pharmaceutical for use in damaged tissue, such as wound, treatment (e.g. healing) is described. The pharmaceutical comprising a composition which comprises: (a) a growth factor; and (b) an inhibitor agent; and optionally (c) a pharmaceutically acceptable carrier, diluent or excipient; wherein the inhibitor agent can inhibit the action of at least one specific adverse protein (e.g. a specific protease) that is upregulated in a damaged tissue, such as a wound, environment.
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- Isoquinolines as urokinase inhibitors
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Compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein one of R1 and R2 is H and the other is N=C(NH2)2 or NHC(=NH)NH2, and the other substituents are as defined herein, are urokinase (uPA) inhibitors.
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- Isoquinolines
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Isoquinolinylguanidine compounds of formula (I): STR1 wherein the substituents are as defined herein, and salts thereof, are disclosed as urokinase inhibitors.
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