Licofelone Suppresses Prostaglandin E2 Formation by Interference with the Inducible Microsomal Prostaglandin E2 Synthase-1

• Published in: The Journal of pharmacology and experimental therapeutics 2008-09, Vol.326 (3), p.975-982
• Main Authors: Koeberle, Andreas, Siemoneit, Ulf, Bühring, Ulrike, Northoff, Hinnak, Laufer, Stefan, Albrecht, Wolfgang, Werz, Oliver
• Format: Article
• Language: English
• Subjects: Adult; Animals; Cattle; Cells, Cultured; Dinoprostone - antagonists & inhibitors; Dinoprostone - biosynthesis; Dose-Response Relationship, Drug; Humans; Intramolecular Oxidoreductases - antagonists & inhibitors; Intramolecular Oxidoreductases - biosynthesis; Microsomes - drug effects; Microsomes - metabolism; Prostaglandin-E Synthases; Pyrroles - pharmacology; Sheep
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.108.139444

The anti-inflammatory drug licofelone [=ML3000; 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1 H -pyrrolizin-5-yl] acetic acid], currently undergoing phase III trials for osteoarthritis, inhibits the prostaglandin (PG) and leukotriene biosynthetic pathway. Licofelone was reported to suppress the formation of PGE 2 in various cell-based test systems, but the underlying molecular mechanisms are not entirely clear. Here, we examined the direct interference of licofelone with enzymes participating in PGE 2 biosynthesis, that is, cyclooxygenase (COX)-1 and COX-2 as well as microsomal PGE 2 synthase (mPGES)-1. Licofelone concentration-dependently inhibited isolated COX-1 (IC 50 = 0.8 μM), whereas isolated COX-2 was less affected (IC 50 > 30 μM). However, licofelone efficiently blocked the conversion of PGH 2 to PGE 2 mediated by mPGES-1 (IC 50 = 6 μM) derived from microsomes of interleukin-1β-treated A549 cells, being about equipotent to 3-[1-(4-chlorobenzyl)-3- t -butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK-886), a well recognized mPGES-1 inhibitor. In intact interleukin-1β-treated A549 cells, licofelone potently (IC 50 < 1 μM) blocked formation of PGE 2 in response to calcimycin (A23187) plus exogenous arachidonic acid, but the concomitant generation of 6-keto PGF 1α , used as a biomarker for COX-2 activity, was not inhibited. We conclude that licofelone suppresses inflammatory PGE 2 formation preferentially by inhibiting mPGES-1 at concentrations that do not affect COX-2, implying an attractive and thus far unique molecular pharmacological dynamics as inhibitor of COX-1, the 5-lipoxygenase pathway, and of mPGES-1.