Cyclooxygenase-1/2 (COX-1/COX-2) and 5-lipoxygenase (5-LOX) inhibitors of the 6,7-diaryl-2,3-1H-dihydropyrrolizine type.
A series of 6,7-diaryl-2,3-1H-dihydropyrrolizines was prepared as COX-1/COX-2 and 5-LOX inhibitors. The inhibition of COX-1 was evaluated using intact bovine platelets as the enzyme source, whereas LPS-stimulated human monocytes served as the enzyme source for inducible COX-2. The determination of arachidonic metabolites was performed by HPLC for COX-1 and RIA for COX-2. The balance between COX-1/COX-2 and 5-LOX inhibition can be shifted by modifying the substitution pattern of the phenyl moiety at the 6- and 7-position of the pyrrolizine nucleus. Structure-activity relationships are discussed.
Ulbrich
Holger
H
Institute of Pharmacy, Johannes Gutenberg-University of Mainz, Staudingerweg 5, D-55099 Mainz, Germany. holger.ulbrich@fyfa.ki.se
Fiebich
Bernd
B
Dannhardt
Gerd
G
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D009000:Monocytes / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases; D011758:Pyrroles / Q000737:chemistry*; D011863:Radioimmunoassay
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011758:Pyrroles; C013231:pyrroline; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases