These results provide further evidence, that ML3000 inhibits 5-LOX as well as COX-1 and COX-2 in vitro and in animal experiments. The favourable gastrointestinal (GI) tolerability of the compound is believed to be linked to the mechanism of combined 5-LOX and COX-1/2 inhibition of ML3000.

No abstract

1 Ibuprofen enantiomers and their respective coenzyme A thioesters were tested in human platelets and blood monocytes to determine their selectivity and potency as inhibitors of cyclo-oxygenase activity of prostaglandin endoperoxide synthase-1 (PGHS-1) and PGHS-2. 2 Human blood from volunteers was drawn and allowed to clot at 378C for 1 h in the presence of increasing concentrations of the test compounds (R-ibuprofen, S-ibuprofen, R-ibuprofenoyl-CoA, Sibuprofenoyl-CoA, NS-398). Immunoreactive (ir) thromboxane B 2 (TXB 2 ) concentrations in serum were determined by a speci®c EIA assay as an index of the cyclo-oxygenase activity of platelet PGHS-1. 3 Heparin-treated blood from the same donors was incubated at 378C for 24 h with the same concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 mg ml 71 ). The contribution of PGHS-1 was suppressed by pretreatment of the volunteers with aspirin (500 mg; 48 h before venepuncture). As a measure of LPS induced PGHS-2 activity immunoreactive prostaglandin E 2 (irPGE 2 ) plasma concentrations were determined by a speci®c EIA assay. 4 S-ibuprofen inhibited the activity of PGHS-1 (IC 50 2.1 mM) and PGHS-2 (IC 50 1.6 mM) equally. Ribuprofen inhibited PGHS-1 (IC 50 34.9) less potently than S-ibuprofen and showed no inhibition of PGHS-2 up to 250 mM. By contrast R-ibuprofenoyl-CoA thioester inhibited PGE 2 production from LPSstimulated monocytes almost two orders of magnitude more potently than the generation of TXB 2 (IC 50 5.6 vs 219 mM). 5 Western blotting of PGHS-2 after LPS induction of blood monocytes showed a concentrationdependent inhibition of PGHS-2 protein expression by ibuprofenoyl-CoA thioesters. 6 These data con®rm that S-ibuprofen represents the active entity in the racemate with respect to cyclooxygenase activity. More importantly the data suggest a contribution of the R-enantiomer to therapeutic eects not only by chiral inversion to S-ibuprofen but also via inhibition of induction of PGHS-2 mediated by R-ibuprofenoyl-CoA thioester. 7 The data may explain why racemic ibuprofen is ranked as one of the safest non-steroidal antiin¯ammatory drugs (NSAIDs) so far determined in epidemiological studies.

No abstract

The synthesis of fluorinated derivatives of the sulphide and sulphone metabolites of sulindac, a non‐steroidal anti‐inflammatory agent with chemopreventative activity, is reported. The key step in the synthesis is a Pummerer‐rearrangement of the parent sulindac sulphoxide using (diethylamino)sulphur trifluoride as an activating agent and as a source of the fluoride nucleophile. The reaction leads to the formation of the 4‐fluoromethylthio and 4‐fluoromethylsulphonyl derivatives of sulindac (4a and 4b, respectively). Sulindac sulphide is 2.5 times more potent as a COX‐1 inhibitor compared with its fluorinated counterpart 4a. The sulphones were inactive as COX‐1 inhibitors, and none of the compounds inhibited COX‐2 concentrations up to 0.1 mM. Cytotoxicity assays showed that 4a and 4b were as cytotoxic as sulindac sulphide and sulindac sulphone on 3719 colorectal carcinoma cell lines. Compound 4b was the most potent compound on RCA cells with an IC50 of 95 μM (sulindac sulphide 140μM, sulindac sulphone 175 μM). Fluorinated sulindac derivatives warrant further investigation since we have shown that cytotoxic activity can be retained or even increased independently from COX‐inhibitory properties. This could help minimize the undesired side‐effects associated with chronic sulindac administration.