Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist, SC-53228: impact upon leukotriene B4- and 12(R)-HETE-mediated events.

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.
AuthorsD 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
JournalInflammation (Inflammation) Vol. 19 Issue 2 Pg. 193-205 (Apr 1995) ISSN: 0360-3997 [Print] UNITED STATES
PMID7601505 (Publication Type: Journal Article)
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
  • 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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