{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T15:50:07Z","timestamp":1770479407753,"version":"3.49.0"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,2,3]],"date-time":"2009-02-03T00:00:00Z","timestamp":1233619200000},"content-version":"vor","delay-in-days":4296,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[1997,5]]},"abstract":"\n\nDFU (5,5\u2010dimethyl\u20103\u2010(3\u2010fluorophenyl)\u20104\u2010(4\u2010methylsulphonyl)phenyl\u20102(5H)\u2010furanone) was identified as a novel orally active and highly selective cyclo\u2010oxygenase\u20102 (COX\u20102) inhibitor.<\/jats:p><\/jats:list-item>\nIn CHO cells stably transfected with human COX isozymes, DFU inhibited the arachidonic acid\u2010dependent production of prostaglandin E2<\/jats:sub> (PGE2<\/jats:sub>) with at least a 1,000 fold selectivity for COX\u20102 (IC50<\/jats:sub>=41\u00b114 nM<\/jats:sc>) over COX\u20101 (IC50<\/jats:sub>>50 \u03bcM<\/jats:sc>). Indomethacin was a potent inhibitor of both COX\u20101 (IC50<\/jats:sub>=18\u00b13 nM<\/jats:sc>) and COX\u20102 (IC50<\/jats:sub>=26\u00b16 nM<\/jats:sc>) under the same assay conditions. The large increase in selectivity of DFU over indomethacin was also observed in COX\u20101 mediated production of thromboxane B2<\/jats:sub> (TXB2<\/jats:sub>) by Ca2+<\/jats:sup> ionophore\u2010challenged human platelets (IC50<\/jats:sub>>50 \u03bcM<\/jats:sc> and 4.1\u00b11.7 nM<\/jats:sc>, respectively).<\/jats:p><\/jats:list-item>\nDFU caused a time\u2010dependent inhibition of purified recombinant human COX\u20102 with a K<\/jats:italic>i<\/jats:sub> value of 140\u00b168 \u03bcM<\/jats:sc> for the initial reversible binding to enzyme and a k<\/jats:italic>2<\/jats:sub> value of 0.11\u00b10.06 s\u22121<\/jats:sup> for the first order rate constant for formation of a tightly bound enzyme\u2010inhibitor complex. Comparable values of 62\u00b126 \u03bcM<\/jats:sc> and 0.06\u00b10.01 s\u22121<\/jats:sup>, respectively, were obtained for indomethacin. The enzyme\u2010inhibitor complex was found to have a 1 : 1 stoichiometry and to dissociate only very slowly (t<\/jats:italic>1\/2<\/jats:sub>=1\u20133 h) with recovery of intact inhibitor and active enzyme. The time\u2010dependent inhibition by DFU was decreased by co\u2010incubation with arachidonic acid under non\u2010turnover conditions, consistent with reversible competitive inhibition at the COX active site.<\/jats:p><\/jats:list-item>\nInhibition of purified recombinant human COX\u20101 by DFU was very weak and observed only at low concentrations of substrate (IC50<\/jats:sub>=63\u00b15 \u03bcM<\/jats:sc> at 0.1 \u03bcM<\/jats:sc> arachidonic acid). In contrast to COX\u20102, inhibition was time\u2010independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX\u20101.<\/jats:p><\/jats:list-item>\nDFU inhibited lipopolysaccharide (LPS)\u2010induced PGE2<\/jats:sub> production (COX\u20102) in a human whole blood assay with a potency (IC50<\/jats:sub>=0.28\u00b10.04 \u03bcM<\/jats:sc>) similar to indomethacin (IC50<\/jats:sub>=0.68\u00b10.17 \u03bcM<\/jats:sc>). In contrast, DFU was at least 500 times less potent (IC50<\/jats:sub>>97 \u03bcM<\/jats:sc>) than indomethacin at inhibiting coagulation\u2010induced TXB2<\/jats:sub> production (COX\u20101) (IC50<\/jats:sub>=0.19\u00b10.02 \u03bcM<\/jats:sc>).<\/jats:p><\/jats:list-item>\nIn a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 \u03bcM<\/jats:sc>), DFU inhibited COX\u20101 with an IC50<\/jats:sub> value of 13\u00b12 \u03bcM<\/jats:sc> as compared to 20\u00b11 nM<\/jats:sc> for indomethacin. CGP 28238, etodolac and SC\u201058125 were about 10 times more potent inhibitors of COX\u20101 than DFU. The order of potency of various inhibitors was diclofenac>indomethacin\u223cnaproxen>nimesulide\u223c meloxicam\u223cpiroxicam>NS\u2010398\u223cSC\u201057666>SC\u201058125>CGP 28238\u223cetodolac>L\u2010745,337>DFU.<\/jats:p><\/jats:list-item>\nDFU inhibited dose\u2010dependently both the carrageenan\u2010induced rat paw oedema (ED50<\/jats:sub> of 1.1 mg kg\u22121<\/jats:sup> vs 2.0 mg kg\u22121<\/jats:sup> for indomethacin) and hyperalgesia (ED50<\/jats:sub> of 0.95 mg kg\u22121<\/jats:sup> vs 1.5 mg kg\u22121<\/jats:sup> for indomethacin). The compound was also effective at reversing LPS\u2010induced pyrexia in rats (ED50<\/jats:sub>=0.76 mg kg\u22121<\/jats:sup> vs 1.1 mg kg\u22121<\/jats:sup> for indomethacin).<\/jats:p><\/jats:list-item>\nIn a sensitive model in which 51<\/jats:sup>Cr faecal excretion was used to assess the integrity of the gastrointestinal tract in rats, no significant effect was detected after oral administration of DFU (100 mg kg\u22121<\/jats:sup>, b.i.d.) for 5 days, whereas chromium leakage was observed with lower doses of diclofenac (3 mg kg\u22121<\/jats:sup>), meloxicam (3 mg kg\u22121<\/jats:sup>) or etodolac (10\u201330 mg kg\u22121<\/jats:sup>). A 5 day administration of DFU in squirrel monkeys (100 mg kg\u22121<\/jats:sup>) did not affect chromium leakage in contrast to diclofenac (1 mg kg\u22121<\/jats:sup>) or naproxen (5 mg kg\u22121<\/jats:sup>).<\/jats:p><\/jats:list-item>\nThe results indicate that COX\u20101 inhibitory effects can be detected for all selective COX\u20102 inhibitors tested by use of a sensitive assay at low substrate concentration. The novel inhibitor DFU shows the lowest inhibitory potency against COX\u20101, a consistent high selectivity of inhibition of COX\u20102 over COX\u20101 (>300 fold) with enzyme, whole cell and whole blood assays, with no detectable loss of integrity of the gastrointestinal tract at doses >200 fold higher than efficacious doses in models of inflammation, pyresis and hyperalgesia. These results provide further evidence that prostanoids derived from COX\u20101 activity are not important in acute inflammatory responses and that a high therapeutic index of anti\u2010inflammatory effect to gastropathy can be achieved with a selective COX\u20102 inhibitor.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p>British Journal of Pharmacology<\/jats:italic> (1997) 121<\/jats:bold>, 105\u2013117; doi:10.1038\/sj.bjp.0701076<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0701076","type":"journal-article","created":{"date-parts":[[2006,8,16]],"date-time":"2006-08-16T14:40:55Z","timestamp":1155739255000},"page":"105-117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":261,"title":["Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX\u20102 inhibitor"],"prefix":"10.1111","volume":"121","author":[{"given":"D","family":"Riendeau","sequence":"first","affiliation":[]},{"given":"M D","family":"Percival","sequence":"additional","affiliation":[]},{"given":"S","family":"Boyce","sequence":"additional","affiliation":[]},{"given":"C","family":"Brideau","sequence":"additional","affiliation":[]},{"given":"S","family":"Charleson","sequence":"additional","affiliation":[]},{"given":"W","family":"Cromlish","sequence":"additional","affiliation":[]},{"given":"D","family":"Ethier","sequence":"additional","affiliation":[]},{"given":"J","family":"Evans","sequence":"additional","affiliation":[]},{"given":"J \u2010P","family":"Falgueyret","sequence":"additional","affiliation":[]},{"given":"A W","family":"Ford\u2010Hutchinson","sequence":"additional","affiliation":[]},{"given":"R","family":"Gordon","sequence":"additional","affiliation":[]},{"given":"G","family":"Greig","sequence":"additional","affiliation":[]},{"given":"M","family":"Gresser","sequence":"additional","affiliation":[]},{"given":"J","family":"Guay","sequence":"additional","affiliation":[]},{"given":"S","family":"Kargman","sequence":"additional","affiliation":[]},{"given":"S","family":"L\u00e9ger","sequence":"additional","affiliation":[]},{"given":"J A","family":"Mancini","sequence":"additional","affiliation":[]},{"given":"G","family":"O'Neill","sequence":"additional","affiliation":[]},{"given":"M","family":"Ouellet","sequence":"additional","affiliation":[]},{"given":"I W","family":"Rodger","sequence":"additional","affiliation":[]},{"given":"M","family":"Th\u00e9rien","sequence":"additional","affiliation":[]},{"given":"Z","family":"Wang","sequence":"additional","affiliation":[]},{"given":"J K","family":"Webb","sequence":"additional","affiliation":[]},{"given":"E","family":"Wong","sequence":"additional","affiliation":[]},{"given":"L","family":"Xu","sequence":"additional","affiliation":[]},{"given":"R N","family":"Young","sequence":"additional","affiliation":[]},{"given":"R","family":"Zamboni","sequence":"additional","affiliation":[]},{"given":"P","family":"Prasit","sequence":"additional","affiliation":[]},{"given":"C \u2010C","family":"Chan","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2009,2,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199209103271101"},{"key":"e_1_2_6_3_1","first-page":"501","article-title":"COX\u20101 and COX\u20102: Toward the development of more selective NSAIDs","volume":"7","author":"Battistini B.","year":"1994","journal-title":"Drug News Perspect."},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0960-894X(95)00512-R"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02265118"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01971260"},{"key":"e_1_2_6_7_1","first-page":"1531","article-title":"Pharmacology of a selective cyclooxygenase\u20102 inhibitor, L\u2010745,337: A novel nonsteroidal anti\u2010inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach","volume":"274","author":"Chan C.\u2010C.","year":"1995","journal-title":"J. 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