Non-steroidal anti-inflammatory agents, Part 19. E-2-pyrrolizin-5-yl acrylic acids as potent dual or selective inhibitors of bovine cyclooxygenase and 5-lipoxygenase

• Published in: Archiv der Pharmazie (Weinheim) Vol. 328; no. 9; p. 681
• Main Authors: Dannhardt, G, Kiefer, W, Nowe, U
• Format: Journal Article
• Language: English
• Published: Germany 1995
• Subjects: Acrylates - chemical synthesis; Acrylates - chemistry; Acrylates - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Blood Platelets - drug effects; Blood Platelets - enzymology; Cattle; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; In Vitro Techniques; Lipoxygenase Inhibitors; Neutrophils - drug effects; Neutrophils - enzymology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Structure-Activity Relationship
• ISSN: 0365-6233
• DOI: 10.1002/ardp.19953280910

The pyrrolizinyl substituted acrylic acid derivatives represent another class of dual and selective inhibitors of cyclooxygenase and 5-lipoxygenase. By modifying their substitution pattern at the phenyl moiety of C-6 the balance between the activity against cyclooxygenase and against 5-lipoxygenase can be shifted. Structure-activity relationships are discussed. Compound 6k is the most potent and well-balanced dual inhibitor of both enzymes, while the highest selectivity of lipoxygenase inhibition was found for 6j. The activity and selectivity of compounds with an additional sulfur moiety depend on the oxidation status of this atom, giving an indication of the discussed coupling between peroxidase and cyclooxygenase. The inhibition of cyclooxygenase was determined in a bovine thrombocyte intact cell assay and that of 5-lipoxygenase using intact bovine PMNLs.