title: Characterization of the in vitro anti-inflammatory activity of AL-5898 and related benzopyranyl esters and amides.
abstract: Selected ester- (AL-5898 and AL-8417) and amide-linked benzopyran analogues (AL-7538 and AL-12615) were evaluated in vitro for their ability to inhibit key enzymes/processes of the inflammatory response. AL-7538 and AL-12615 exhibited weak intrinsic cyclooxygenase inhibitory activity (IC50 = 13 microM, 37 microM). In contrast, 5-HETE and LTB4 synthesis in A(23187)-stimulated neutrophils was effectively inhibited by both ester and amide analogs (IC50 = 2-3 microM). While there was some indication for differing sensitivities among benzopyran esters and amides in the suppression of cytokine synthesis in stimulated U-937 cells, there appeared to be no great discrimination when assessing their effect on U-937 cell adhesion to IL-1beta activated HMVEC-L cells. Inhibition of cell adhesion was concentration-dependent, with IC50 values ranging between 18 microM and 30 microM for AL-5898. Concentration-dependent inhibition of inflammatory cytokine production (i.e., IL-1beta, TNF-alpha, GM-CSF and IL-6) was also apparent in LPS-stimulated, cultured PBMC as well as in PMA/A(23187) activated U-937 cells monitoring the synthesis of IL-1beta, IL-8, TNF-alpha, and MCP-1. Notably, the hydrolysis products of the benzopyranyl ester, AL-5692 and (S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, were devoid of pharmacological activity when assessed for inhibition of monocyte adhesion or IL-1beta synthesis. Collectively, our data demonstrate the unique in vitro polypharmacology of a novel series of benzopyran analogs that suppress pivotal enzymes and processes in the inflammatory response.
authors.affiliation: Pharmaceutical Products Research, Alcon Research, Ltd., 6201 S. Freeway, Fort Worth, TX 76134-2099, USA.
authors.forename: Karen C
authors.initials: KC
authors.lastname: David
authors.forename: Milton T
authors.initials: MT
authors.lastname: Brady
authors.forename: Lori K
authors.initials: LK
authors.lastname: Weimer
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellberg
authors.forename: Jon C
authors.initials: JC
authors.lastname: Nixon
authors.forename: Gustav
authors.initials: G
authors.lastname: Graff
mesh_terms: D000577:Amides; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002675:Child, Preschool; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D004952:Esters; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009288:Naproxen / Q000494:pharmacology*; D018375:Neutrophil Activation; D020298:U937 Cells
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D004952:Esters; D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D009288:Naproxen