Discovery of 7‐Aryl‐Substituted (1,5‐Naphthyridin‐4‐yl)ureas as Aurora Kinase Inhibitors |
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Authors: | Dr Julien Defaux Dr Maud Antoine Prof Marc Le?Borgne Dr Tilmann Schuster Dr Irene Seipelt Dr Babette Aicher Dr Michael Teifel Dr Eckhard Günther Dr Matthias Gerlach Prof Pascal Marchand |
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Affiliation: | 1. Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer IICiMed EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes (France);2. Current address: AtlanChim Pharma, 3 rue Aronnax, 44821 Saint Herblain Cedex (France);3. Current address: Université de Lyon, Université Lyon 1, Faculté de Pharmacie‐ISPB, EA 4446 Biomolécules Cancer et Chimiorésistances, SFR Santé Lyon‐Est CNRS UMS3453‐INSERM US7, 8 avenue Rockefeller, 69373 Lyon Cedex 8 (France);4. ?terna Zentaris GmbH, Weismuellerstrasse 50, 60314 Frankfurt/Main (Germany) |
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Abstract: | As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7‐aryl‐1,5‐naphthyridin‐4‐yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5‐Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1‐cyclopropyl‐3‐7‐(1‐methyl‐1H‐pyrazol‐4‐yl)‐1,5‐naphthyridin‐4‐yl]urea ( 49 ), displayed IC50 values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer‐related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents. |
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Keywords: | 1 5‐naphthyridines aurora kinases heterocycles inhibitors ureas |
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