Cyclooxygenase-2 inhibitors assays

Several interesting findings dealing with 2-quinolinylmethyl esters related to Rev 5901A (139) have been reported. Workers at Wyeth-Ayerst found that attachment of this moeity to a number of classical NSAIDs endowed these cyclooxygenase inhibitors with 5-LO inhibitory activity in cell assays... 

Berg, J., Christoph, T., Widerna, M., Bodenteich, A. Isoenzyme-specific cyclooxygenase inhibitors a whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell line Mono Mac 6, J. Pharmacol. Toxicol. Methods 1997, 37, 179-186. 

In in vitro anterior pituitary assay systems prostaglandins do not stimulate basal LH release and cyclooxygenase inhibitors do not inhibit LHRH-stimulated LH release... 

Chan et al. (1995), Riendeau et al. (1997) used a fecal 51 Cr excretion assay in rats and primates to detect gastrointestinal integrity after application of a selective cyclooxygenase inhibitor. 

Fig. 6. Effects of cyclooxygenase inhibitors on lipopolysaccharide (LPS)-induced tumor necrosis-factor (TNF)-a production. THP-1 cells pretreated with indomethacin (5 pM), niflumic acid (2 pM) or aspirin (2 mM) were stimulated with EPS for 6 h. TNF-a levels in cell culture supernatant were determined by enzyme-linked immunosorbent assay. The amount of TNF-a produced in the control LPS-stimulated cells is set as 100%. Values are means SEM, n = 3. The treated groups did not differ from the control group. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Mazenko, R.S. Skarbek, A. Woolf, E.J. Simpson, R.C. Matuszewski, B. Sample Preparation via Solid Phase Extraction in the 96-Well Form for HPLC/UV Detection-Based Biofluid Assays. Application to the Determination of a Novel Cyclooxygenase II Inhibitor in Human Plasma and Urine, J. Liq. Chrom. 24(17), 2601-2614 (2001). 

Indoprofen In a high-throughput screen of ca. 47,000 compound library, authors [43] have converged on indoprofen as a molecule that enhanced production of an SMN2- vs. SMN1 -luciferase reporter protein. Indoprofen, a NSAID and cyclooxygenase (COX) inhibitor, afforded a 13% enhancement of Smn protein and a fivefold increase in the number of nuclear gems in fibroblasts from SMA patients. Notably, other tested NSAIDs or COX inhibitors were inactive in the assay. 

Three 4-thiazolidinone libraries were prepared and assayed for inhibition of the enzyme cyclooxygenase-1 (COX-1), a key enzyme in the conversion of arachidonic acid to prostaglandins [421, 422], From the carboxylic acid, ester and carboxamides libraries only the methyl ester library showed significant activity. A series of three rounds of testing and deconvolution led to a compound (library 37 IC50 3.7 fiM) with equivalent in vitro activity to the commercially available COX-1 inhibitors ibuprofen and phenylbutazone. 

The selectivity of drugs is generally assessed with the aid of in vitro or ex-vivo assay systems, and also in human whole blood as appropriate. Occasionally, however, the data show considerable variability. This appears to apply in particular to meloxicam, where, depending on the experimental set-up, almost any selectivity factor may be obtained. [188] COX- inhibitors show in general affinity to both isozymes, cyclooxygenase-1 and -2. In many cases the selectivity factor ranges from 1 to 100 (Fig. 5.90). [189]... 

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