title: Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3.
abstract: The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the number of off-targets. The most promising covalent inhibitor, the tetrasubstituted imidazole 3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (7) inhibits the JNK3 in the subnanomolar range (IC50= 0.3 nM), shows high metabolic stability in human liver microsomes, and displays excellent selectivity in a screening against a panel of 410 kinases. Covalent bond formation to Cys-154 was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry.
authors.affiliation: Department of Pharmaceutical 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.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Chemistry Department, Faculty of Science, Menofia University , Menofia, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Gokha
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ansideri
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Eitel
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Döring
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Sievers-Engler
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lange
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Boeckler
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lämmerhofer
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Pierre
authors.initials: P
authors.lastname: Koch
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Stefan A
authors.identifier: 0000-0001-6952-1486
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000620968:3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide; D000178:Acrylamides; D001549:Benzamides; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048057:Mitogen-Activated Protein Kinase 10