Document Detail


Tetrasubstituted imidazole inhibitors of cytokine release: probing substituents in the N-1 position.
MedLine Citation:
PMID:  15566301     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Stefan A Laufer; Werner Zimmermann; Kathrin J Ruff
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  47     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-29     Completed Date:  2005-01-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6311-25     Citation Subset:  IM    
Affiliation:
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
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MeSH Terms
Descriptor/Qualifier:
Aminopyridines / chemical synthesis*,  chemistry,  pharmacology
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*,  chemistry,  pharmacology
Binding Sites
Cytochrome P-450 Enzyme System / antagonists & inhibitors,  chemistry
Cytokines / antagonists & inhibitors*,  blood
Humans
Imidazoles / chemical synthesis*,  chemistry,  pharmacology
Interleukin-1 / antagonists & inhibitors,  blood
Isoenzymes / antagonists & inhibitors,  chemistry
Models, Molecular
Molecular Conformation
Pyridines / chemistry,  pharmacology
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*,  chemistry
Chemical
Reg. No./Substance:
0/Aminopyridines; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Cytokines; 0/Imidazoles; 0/Interleukin-1; 0/Isoenzymes; 0/N-(4-(5-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methylsulfanyl-3H-imidazol-4-yl)pyridin-2-yl)acetamide; 0/Pyridines; 0/SB 203580; 0/Tumor Necrosis Factor-alpha; 9035-51-2/Cytochrome P-450 Enzyme System; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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