Abstract |
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.
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Authors | D J Fretland, C P Anglin, M Bremer, P Isakson, D L Widomski, S K Paulson, S H Docter, S W Djuric, T D Penning, S Yu |
Journal | Inflammation
(Inflammation)
Vol. 19
Issue 2
Pg. 193-205
(Apr 1995)
ISSN: 0360-3997 [Print] United States |
PMID | 7601505
(Publication Type: Journal Article)
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Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Benzamides
- Benzopyrans
- Biomarkers
- Hydroxyeicosatetraenoic Acids
- Receptors, Leukotriene B4
- SC 41930
- 7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid
- Leukotriene B4
- 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
- Peroxidase
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Topics |
- 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
- Administration, Oral
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(administration & dosage, pharmacology)
- Benzamides
(administration & dosage, pharmacology)
- Benzopyrans
(administration & dosage, pharmacology)
- Biomarkers
- Chemotaxis, Leukocyte
(drug effects)
- Granulocytes
(drug effects)
- Guinea Pigs
- Hydroxyeicosatetraenoic Acids
(administration & dosage, pharmacology)
- Injections, Intradermal
- Leukotriene B4
(administration & dosage, pharmacology)
- Male
- Membrane Potentials
(drug effects)
- Neutrophils
(drug effects, enzymology)
- Peroxidase
(analysis)
- Receptors, Leukotriene B4
(antagonists & inhibitors, physiology)
- Skin
(drug effects, immunology, pathology)
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