title: CP-66,248, a new anti-inflammatory agent, is a potent inhibitor of leukotriene B4 and prostanoid synthesis in human polymorphonuclear leucocytes in vitro.
abstract: The effects of (Z)-5-chloro-2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-oxo-1H- indole-1-carboxamide (CP-66,248), a new anti-inflammatory agent, were tested on the synthesis of the pro-inflammatory arachidonic acid metabolites, LTB4 and PGE2, in isolated human peripheral polymorphonuclear leucocytes. At clinically achievable (i.e. plasma) drug concentration, CP-66,248 reduced A 23187-stimulated LTB4 (IC50 18 +/- 1 microM) and PGE2 (IC50 32 +/- 8 nM) synthesis. The corresponding IC50 values for arachidonic acid-induced LTB4 and PGE2 production were 13 +/- 4 microM and 65 +/- 15 nM, respectively. The inhibitory action of CP-66,248 towards 5-lipoxygenase was comparable with that of timegadine and exceeded that of caffeic acid, and its action against the cyclo-oxygenase pathway was similar to that of other NSAIDs tested. The dual inhibition of cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism is likely to be involved in the anti-inflammatory, antipyretic and analgetic action of CP-66,248 detected in a variety of experimental models.
authors.affiliation: Department of Biomedical Sciences, University of Tampere, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Moilanen
authors.forename: J
authors.initials: J
authors.lastname: Alanko
authors.forename: M Z
authors.initials: MZ
authors.lastname: Asmawi
authors.forename: H
authors.initials: H
authors.lastname: Vapaatalo
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000096:biosynthesis* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D000078183:Oxindoles; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013929:Thromboxane B2 / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D000078183:Oxindoles; D007975:Leukotriene B4; D000001:Calcimycin; D013929:Thromboxane B2; C062866:tenidap; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone