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.
Fretland
D J
DJ
Department of Inflammatory Diseases Research, Searle Research and Development, Chesterfield, Missouri, USA.
Anglin
C P
CP
Bremer
M
M
Isakson
P
P
Widomski
D L
DL
Paulson
S K
SK
Docter
S H
SH
Djuric
S W
SW
Penning
T D
TD
Yu
S
S
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006098:Granulocytes / Q000187:drug effects; D006168:Guinea Pigs; D006893:Hydroxyeicosatetraenoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D007271:Injections, Intradermal; D007975:Leukotriene B4 / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009195:Peroxidase / Q000032:analysis; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D001578:Benzopyrans; D015415:Biomarkers; D006893:Hydroxyeicosatetraenoic Acids; D018102:Receptors, Leukotriene B4; C059950:SC 41930; C082206:7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid; D007975:Leukotriene B4; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D009195:Peroxidase