title: Substituted isoxazoles as potent inhibitors of p38 MAP kinase.
abstract: In a continuous effort to develop improved p38 MAP (mitogen-activated protein) kinase inhibitors, we focused our attention on the suitability of the isoxazole ring as a bioisosteric replacement for the imidazole ring of SB-203580. 3,4- and 4,5-disubstituted as well as 3,4,5-trisubstituted isoxazole derivatives were synthesized. These compounds were tested in an in vitro enzyme-linked immunosorbent assay of isolated p38 MAP kinase and for inhibitory potency against cytochrome P450. Compound 4 a displays a highly promising profile for development as an anti-inflammatory agent owing to its enhanced suppression of cytokine release, decreased affinity for cytochrome P450 and a twofold decrease in IC50 toward isolated p38 MAP kinase.
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard Karls University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. stefan.laufer@uni-tuebingen.de
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
authors.forename: Simona
authors.initials: S
authors.lastname: Margutti
authors.forename: Martina D
authors.initials: MD
authors.lastname: Fritz
mesh_terms: D008401:Gas Chromatography-Mass Spectrometry; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007555:Isoxazoles; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases