Original Article

Inhibitory effect of 3,4-diaryl-3-pyrrolin-2-one derivatives on cyclooxygenase 1 and 2 in murine peritoneal macrophages.

Authors: Fang SHEN, Ai-Ping BAI, Zong-Ru GUO, Gui-Fang CHENG

Abstract

AIM: To develop a whole-cell assay based on murine peritoneal macrophages and
evaluate the inhibitory effect of candidate compounds on cyclooxygenase-1 (COX-1)
and COX-2.
METHODS: Macrophages were stimulated with calcimycin or lipopolysaccharide (LPS)
for various periods. Their abilities to convert endogenous arachidonic acid to
6-keto-PGF1alpha or PGE2 were examined by radioimmunoassay (RIA). RNA level of
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and COX-1/2 was detected by
reverse transcription polymerase chain reaction (RT-PCR) using specific primers.
RESULTS: Rofecoxib selectively inhibited LPS-induced, COX-2-derived PGE2
synthesis with an IC50 value of (4.7+/-0.5) nmol/L compared with maximum
inhibitory ratio of 17.3 % for the inhibition of calcimycin induced,
COX-1-derived 6-keto-PGF1alpha synthesis. Indomethacin exhibited dual inhibitory
effects on COX-1 and COX-2 with IC50 of (4.7+/-1.1) nmol/L and (7.1+/-1.2)
nmol/L, respectively. Two series of 17 compounds were tested. Most of compounds
in series II showed comparable inhibitory activities to rofecoxib on COX-2. The
relative position of the sulfonylphenyl group to the lactam carbonyl group has
important effects on COX-2 inhibitory activity.
CONCLUSION: The established whole cell assay is appropriate for drug-design
oriented in vitro assay. 3,4-Diaryl-3-pyrrolin-2-one derivatives were proved to
be prospective new type of COX-2 selective inhibitors.
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