title: Syntheses and structure-activity relationships for some triazolyl p38α MAPK inhibitors.
abstract: The design, synthesis and biological evaluation of novel triazolyl p38α MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups were introduced via a 'click' reaction of functional azides with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted 1,2,3-triazolyl p38α MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical properties were screened for in vitro downregulation of proinflammatory gene expression and were formulated in SAINT-O-Somes. Triazolyl p38α MAPK inhibitor 88 (IC50=0.096 μM) displayed the most promising in vitro activity.
authors: Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands. Electronic address: j.p.g.seerden@syncom.nl.
authors: Jean-Paul G
authors: JP
authors: Seerden
authors: Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands.
authors: Gabriela
authors: G
authors: Leusink-Ionescu
authors: Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands.
authors: Robin
authors: R
authors: Leguijt
authors: Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands.
authors: Catherine
authors: C
authors: Saccavini
authors: Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands.
authors: Edith
authors: E
authors: Gelens
authors: Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands.
authors: Bas
authors: B
authors: Dros
authors: Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors: Titia
authors: T
authors: Woudenberg-Vrenken
authors: Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors: Grietje
authors: G
authors: Molema
authors: Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors: Jan A A M
authors: JA
authors: Kamps
authors: Syncom B.V., Kadijk 3, Groningen 9747AT, The Netherlands.
authors: Richard M
authors: RM
authors: Kellogg
mesh_terms: D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D014867:Water; D048051:p38 Mitogen-Activated Protein Kinases
keywords: COX-2, IL-6; Inflammation; Triazole; p38α MAPK inhibitors