title: Synthesis and structure-activity relationships of 4-fluorophenyl-imidazole p38α MAPK, CK1δ and JAK2 kinase inhibitors.
abstract: The synthesis and structure-activity relationships of novel 4-(4'-fluorophenyl)imidazoles as selective p38α MAPK, CK1δ and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via 'click' reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38α MAPK with IC50=250 nM and 96 nM, respectively. Pyridine 3 gave CK1δ inhibition with IC50=89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50=62 nM.
authors.affiliation: Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands. Electronic address: j.p.g.seerden@syncom.nl.
authors.forename: Jean-Paul G
authors.initials: JP
authors.lastname: Seerden
authors.affiliation: Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Leusink-Ionescu
authors.affiliation: Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Titia
authors.initials: T
authors.lastname: Woudenberg-Vrenken
authors.affiliation: Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Dros
authors.affiliation: Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.affiliation: Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Jan A A M
authors.initials: JA
authors.lastname: Kamps
authors.affiliation: Syncom B.V., Kadijk 3, Groningen 9747 AT, The Netherlands.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Kellogg
mesh_terms: D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D014230:Triazoles; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D048148:Casein Kinase Idelta; D020928:Mitogen-Activated Protein Kinases
keywords: 4-Fluorophenyl-imidazole; Alkyne-azide click reaction; Aqueous solubility; Multicomponent reactions; p38α MAPK, CK1δ, JAK2 inhibitors