title: Discovery of 7-aryl-substituted (1,5-naphthyridin-4-yl)ureas as aurora kinase inhibitors.
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.
authors.affiliation: 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).
authors.forename: Julien
authors.initials: J
authors.lastname: Defaux
authors.forename: Maud
authors.initials: M
authors.lastname: Antoine
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.forename: Tilmann
authors.initials: T
authors.lastname: Schuster
authors.forename: Irene
authors.initials: I
authors.lastname: Seipelt
authors.forename: Babette
authors.initials: B
authors.lastname: Aicher
authors.forename: Michael
authors.initials: M
authors.lastname: Teifel
authors.forename: Eckhard
authors.initials: E
authors.lastname: Günther
authors.forename: Matthias
authors.initials: M
authors.lastname: Gerlach
authors.forename: Pascal
authors.initials: P
authors.lastname: Marchand
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D045325:HCT116 Cells; D006207:Half-Life; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009287:Naphthyridines / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D014508:Urea; D064096:Aurora Kinase A; D064107:Aurora Kinase B
keywords: 1,5-naphthyridines; aurora kinases; heterocycles; inhibitors; ureas