title: Synthesis and biological evaluation of a triazole-based library of pyrido[2,3-d]pyrimidines as FGFR3 tyrosine kinase inhibitors.
abstract: A library of pyrido[2,3-d]pyrimidines was designed as inhibitors of FGFR3 tyrosine kinase allowing possible interactions with an unexploited region of the ATP binding-site. This library was built-up with an efficient step of click-chemistry giving easy access to triazole-based compounds bearing a large panel of substituents. Among the 27 analogues synthesized, more than half exhibited 55-89% inhibition of in vitro FGFR3 kinase activity at 2 microM and one (19g) was able to inhibit auto-phosphorylation of mutant FGFR3-K650M in transfected HEK cells.
authors.affiliation: Université Paris Descartes, UMR 8601-CNRS, 45 rue des Saints-Pères, 75006 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Le Corre
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Girard
authors.forename: Johannes
authors.initials: J
authors.lastname: Aubertin
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.forename: Catherine
authors.initials: C
authors.lastname: Benoist-Lasselin
authors.forename: Aurélie
authors.initials: A
authors.lastname: Jonquoy
authors.forename: Emilie
authors.initials: E
authors.lastname: Mugniery
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
authors.forename: Patricia
authors.initials: P
authors.lastname: Busca
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Merrer
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: C573238:1-tert-butyl-3-(6-(3,5-dimethoxyphenyl)-2-((1-((1-methylpiperidin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methylamino)pyrido(2,3-d)pyrimidin-7-yl)urea; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D014230:Triazoles; D011505:Protein-Tyrosine Kinases