Multiple actions of the leukotriene B4 receptor antagonist SC-41930.
7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl-2H-1-benzopyran-2-carboxylic acid (SC-41930), a leukotriene B4 (LTB4) receptor antagonist with anti-inflammatory activity in animal models of colitis, was evaluated for effects on superoxide, LTB4 and prostaglandin E2 production. SC-41930 inhibited human neutrophil (PMN) superoxide generation maximally stimulated by f-Met-Leu-Phe (IC50 4 microM) and C5a (IC50 approximately 12 microM). Moreover, postreceptor stimulation of superoxide production by NaF (a G protein activator), but not by phorbol myristate acetate, was significantly inhibited by SC-41930, indicating that SC-41930 may act via attenuation of a G protein-mediated signal transduction. SC-41930 also inhibited A23187-stimulated LTB4 production (IC50 5.3 microM) in human PMN as well as LTB4 (IC50 2.1 microM) and prostaglandin E2 (IC50 2.9 microM) production in HL-60 cells. When coinjected intradermally (400 micrograms/site), SC-41930 inhibited A23187-stimulated increases in LTB4 levels in guinea pig skin. SC-41930 inhibited human synovial phospholipase A2 (IC50 72 microM), A23187-stimulated 5-hydroxy-eicosatetranoic acid production in human PMN (IC50 8.5 microM), and rat peritoneal leukotriene A4 hydrolase (IC50 20 microM), but not ram seminal vesical cyclooxygenase. The results suggest that the anti-inflammatory activity of SC-41930 could be attributed to postreceptor inhibition of inflammatory mediator production by PMN and other cells in addition to antagonism of PMN LTB4 receptors.
Villani-Price
D
D
Gastrointestinal Diseases Research, Searle Research and Development, Skokie, Illinois.
Yang
D C
DC
Walsh
R E
RE
Fretland
D J
DJ
Keith
R H
RH
Kocan
G
G
Kachur
J F
JF
Gaginella
T S
TS
Tsai
B S
BS
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D015777:Eicosanoids / Q000096:biosynthesis; D004851:Epoxide Hydrolases / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000187:drug effects; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018102:Receptors, Leukotriene B4; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001578:Benzopyrans; D015777:Eicosanoids; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D013481:Superoxides; C059950:SC 41930; D007975:Leukotriene B4; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D004851:Epoxide Hydrolases; D015232:Dinoprostone; C043134:leukotriene A4 hydrolase