228252-34-4Relevant academic research and scientific papers
Design and Synthesis of Fsp3-Rich, Bis-Spirocyclic-Based Compound Libraries for Biological Screening
Stotani, Silvia,Lorenz, Christoph,Winkler, Matthias,Medda, Federico,Picazo, Edwige,Ortega Martinez, Raquel,Karawajczyk, Anna,Sanchez-Quesada, Jorge,Giordanetto, Fabrizio
, p. 330 - 336 (2016/07/06)
The exploration of innovative chemical space is a critical step in the early phases of drug discovery. Bis-spirocyclic frameworks occur in natural products and other biologically relevant metabolites and show attractive features, such as molecular compactness, structural complexity, and three-dimensional character. A concise approach to the synthesis of bis-spirocyclic-based compound libraries starting from readily available commercial reagents and robust chemical transformations has been developed. A number of novel bis-spirocyclic scaffold examples, as implemented in the European Lead Factory project, is presented.
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.
