Tetrasubstituted imidazole inhibitors of cytokine release: probing substituents in the N-1 position.
We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-activated protein kinase p38 (p38 IC(50) = 0.218 microM) as well as the release of the proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) from human whole blood after stimulation with LPS. Furthermore, compound 9b exhibited reduced cytochrome P450 interaction in comparison with SB203580. This result is particularly important, since cytochrome P450 interaction is observed for some p38 inhibitors and in turn can potentially cause drug-drug interaction or lead to other hepatic changes such as P450 enzyme induction.
Laufer
Stefan A
SA
Department of Pharmacy, Institute of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. stefan.laufer@uni-tuebingen.de
Zimmermann
Werner
W
Ruff
Kathrin J
KJ
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000631:Aminopyridines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065607:Cytochrome P-450 Enzyme Inhibitors; D016207:Cytokines; D007093:Imidazoles; D007375:Interleukin-1; D007527:Isoenzymes; C494723:N-(4-(5-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methylsulfanyl-3H-imidazol-4-yl)pyridin-2-yl)acetamide; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580