title: A frozen analogue approach to aminopyridinylimidazoles leading to novel and promising p38 MAP kinase inhibitors.
abstract: In this study we report the design, synthesis, and biological evaluation of constrained aminopyridinylimidazoles as p38α MAP kinase inhibitors. The frozen analogue approach focused on the pyridinyl unit, using purine bioisosteres as constrained structure analogues. The identification of the most potent bioisostere was followed by a further derivatization to address hydrophobic region II. In combination with C-2 modifications of the imidazole core, we were able to design highly active inhibitors on the p38α MAP kinase. The inhibitor design presented herein represents a promising and highly efficient advancement of recent stages of development in this class of p38 MAP kinase inhibitors. In combination with the highly flexible synthetic strategy, directions toward further investigations of complex C-5 modifications of diarylimidazoles are indicated.
authors.affiliation: Department of Medicinal Chemistry, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Selig
authors.forename: Marcia
authors.initials: M
authors.lastname: Goettert
authors.forename: Verena
authors.initials: V
authors.lastname: Schattel
authors.forename: Dieter
authors.initials: D
authors.lastname: Schollmeyer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Albrecht
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
mesh_terms: D015195:Drug Design; D019277:Entropy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011687:Purines / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D011687:Purines; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases