942119-65-5Relevant articles and documents
Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors
Becker, Michael R.,Ewing, William R.,Davis, Roderick S.,Pauls, Henry W.,Ly, Cuong,Li, Aiwen,Mason, Helen J.,Choi-Sledeski, Yong Mi,Spada, Alfred P.,Chu, Valeria,Brown, Karen D.,Colussi, Dennis J.,Leadley, Robert J.,Bentley, Ross,Bostwick, Jeff,Kasiewski, Charles,Morgan, Suzanne
, p. 2753 - 2758 (1999)
Thienopyridine sulfonamide pyrrolidinones were found to be potent and selective inhibitors of the coagulation cascade enzyme factor Xa. SAR studies led to several compounds that were selected for further in vivo investigation. These novel aryl binding pocket moieties represent a structural modification to a series of fXa inhibitors. Several compounds proved to be efficacious iv antithrombotic agents.
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,O'Gara, Margaret,McCleverty, Dawn,McIntosh, Fraser,Phillips, Christopher,Webster, Robert
, p. 2341 - 2351 (2008/02/03)
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.
