title: Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of neurodegenerative diseases.
abstract: Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinase (JNK) 3 and p38α mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α MAP kinase inhibitors are 6m (IC50: JNK3, 18 nM; p38α, 30 nM) and 14d (IC50: JNK3, 26 nM; p38α, 34 nM) featuring both excellent solubility and metabolic stability. They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington's disease.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Muth
authors.forename: Marcel
authors.initials: M
authors.lastname: Günther
authors.forename: Silke M
authors.initials: SM
authors.lastname: Bauer
authors.forename: Eva
authors.initials: E
authors.lastname: Döring
authors.forename: Sabine
authors.initials: S
authors.lastname: Fischer
authors.forename: Julia
authors.initials: J
authors.lastname: Maier
authors.forename: Peter
authors.initials: P
authors.lastname: Drückes
authors.forename: Jürgen
authors.initials: J
authors.lastname: Köppler
authors.forename: Jörg
authors.initials: J
authors.lastname: Trappe
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rothbauer
authors.forename: Pierre
authors.initials: P
authors.lastname: Koch
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D054852:Small Molecule Libraries; D048057:Mitogen-Activated Protein Kinase 10; D048308:Mitogen-Activated Protein Kinase 14