Multi-dimensional target profiling of N,4-diaryl-1,3-thiazole-2-amines as potent inhibitors of eicosanoid metabolism.

Abstract

Eicosanoids like leukotrienes and prostaglandins play a considerable role in inflammation. Produced within the arachidonic acid (AA) cascade, these lipid mediators are involved in the pathogenesis of pain as well as acute and chronic inflammatory diseases like rheumatoid arthritis and asthma. With regard to the lipid cross-talk within the AA pathway, a promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Within this study, thirty N-4-diaryl-1,3-thiazole-2-amine based compounds with different substitution patterns were synthesized and tested in various cell-based assays to investigate their activity and selectivity profile concerning five key enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1/-2)). With compound 7, 2-(4-phenyl)thiazol-2-ylamino)phenol (ST-1355), a multi-target ligand targeting all tested enzymes is presented, whereas compound 9, 2-(4-(4-chlorophenyl)thiazol-2-ylamino)phenol (ST-1705), represents a potent and selective 5-LO and COX-2 inhibitor with an IC50 value of 0.9 ± 0.2 μM (5-LO) and a residual activity of 9.1 ± 1.1% at 10 μM (COX-2 product formation). The promising characteristics and the additional non-cytotoxic profile of both compounds reveal new lead structures for the treatment of eicosanoid-mediated diseases.

• Authors: Carmen B Rödl, Dominik Vogt, Simon B M Kretschmer, Katja Ihlefeld, Sebastian Barzen, Astrid Brüggerhoff, Janosch Achenbach, Ewgenij Proschak, Dieter Steinhilber, Holger Stark, Bettina Hofmann
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 84 Pg. 302-11 (Sep 12 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 25036790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• 2-(4-(4-chlorophenyl)thiazol-2-ylamino)phenol
• 2-(4-phenyl)thiazol-2-ylamino)phenol
• 5-Lipoxygenase-Activating Proteins
• Aminophenols
• Eicosanoids
• Enzyme Inhibitors
• Thiazoles
• Cyclooxygenase 2

Topics

• 5-Lipoxygenase-Activating Proteins (metabolism)
• Aminophenols (chemical synthesis, chemistry, pharmacology)
• Cyclooxygenase 2 (metabolism)
• Dose-Response Relationship, Drug
• Eicosanoids (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• HeLa Cells
• Humans
• Molecular Structure
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry, pharmacology)
• Tumor Cells, Cultured
• U937 Cells