Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist, SC-53228: impact upon leukotriene B4- and 12(R)-HETE-mediated events
| Autor: | D. J. Fretland, J. P. McKearn, M. Bremer, Stephen H. Docter, S. K. Paulson, S. W. Djuric, D. L. Widomski, Stella S. Yu, T. D. Penning, C. P. Anglin, Peter C. Isakson |
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| Rok vydání: | 1995 |
| Předmět: |
Male
Injections Intradermal Leukotriene B4 medicine.drug_class Neutrophils Immunology Guinea Pigs Receptors Leukotriene B4 Administration Oral Pharmacology Proinflammatory cytokine Membrane Potentials chemistry.chemical_compound Hydroxyeicosatetraenoic Acids medicine Immunology and Allergy Animals Benzopyrans Granulocyte chemotaxis 12-Hydroxy-5 8 10 14-eicosatetraenoic Acid Peroxidase Skin biology Leukotriene B4 receptor Anti-Inflammatory Agents Non-Steroidal Antagonist Chemotaxis Receptor antagonist Chemotaxis Leukocyte chemistry Myeloperoxidase Benzamides biology.protein lipids (amino acids peptides and proteins) Biomarkers Granulocytes |
| Zdroj: | Inflammation. 19(2) |
| ISSN: | 0360-3997 |
| Popis: | Leukotriene B4 (LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig. LTB4 and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihy dro-8-propyl-2H - 1-benzopyran-2-carboxylic acid), a first-generation LTB4 receptor antagonist, inhibited the chemotactic actions of LTB4 when given orally with an ED50 value of 1.7 mg/kg. The second-generation LTB4 receptor antagonist, SC-53228 [(+)-(S)-7-(3-(2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], inhibited LTB4-induced chemotaxis when given intragastrically with an ED50 value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED50 value of 5.8 mg/kg. When dosed orally over a range of 0.03-100 mg/kg, SC-53228 gave Cmax plasma concentrations of 0.015-41.1 micrograms/ml. SC-53228 inhibited LTB4-primed membrane depolarization of human neutrophils with an IC50 value of 34 nM. As a potent LTB4 receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB4 and/or 12(R)-HETE are implicated as inflammatory mediators. |
| Databáze: | OpenAIRE |
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