An optimized and versatile synthesis to pyridinylimidazole-type p38α mitogen activated protein kinase inhibitors.
An optimized strategy for the synthesis of the potent p38α mitogen-activated protein kinase inhibitors 2-(2-hydroxyethylsulfanyl)-4-(4-fluorophenyl)-5-(2-aminopyridin-4-yl)imidazole (3) and 2-(2,3-dihydroxypropylsulfanyl)-4-(4-fluorophenyl)-5-(2-aminopyridin-4-yl)imidazole (4) starting from 2-fluoro-4-methylpyridine is reported. In contrast to a previously published synthesis starting from 2-bromo-4-methylpyridine, the overall yield could be increased from 3.6% to 29.4%. Moreover, this strategy avoids the use of palladium as a catalyst and is more diverse and versatile. Using this optimized protocol, both enantiomers of potent inhibitor 3 were synthesized. Biological data demonstrated that the (S)-enantiomer is the two times more potent eutomer.
Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. pierre.koch@uni-tuebingen.de and Menofia University, Chemistry Department, Faculty of Science, Menofia, Egypt.
Ahmed
A
El-Gokha
Institute of Pharmaceutical Sciences, Chair for Medicinal and Pharmaceutical Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Stefan A
SA
Laufer
Institute of Pharmaceutical Sciences, Department of Medicinal and Pharmaceutical Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. pierre.koch@uni-tuebingen.de.
Pierre
P
Koch
D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
D000631:Aminopyridines; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; C029899:imidazole; D048308:Mitogen-Activated Protein Kinase 14; C032439:alpha-aminopyridine