The in vitro pharmacology of SC-51146: a potent antagonist of leukotriene B4 receptors.
Previously, we reported that SC-41930 is a potent leukotriene B4 (LTB4) receptor antagonist. An analog of SC-41930, SC-51146, was evaluated as an antagonist of LTB4 receptors. SC-51146 was shown to bind to LTB4 high affinity binding sites on human neutrophils (PMN) with a dissociation constant (KD) value of 1.5 +/- 0.1 nM, compared to 19 +/- 1.3 nM for SC-41930. PMN chemotaxis studies and Scatchard analyses of [3H]LTB4 binding in PMN membranes indicated that SC-51146 acted as a competitive antagonist. The IC50 value of SC-51146 for the inhibition of PMN chemotaxis induced by 30 nM LTB4 was 38 +/- 12 nM. SC-51146 inhibited PMN degranulation induced by 50 nM LTB4 with an IC50 value of 29 +/- 7 nM. The antagonism by SC-51146 of LTB4-induced PMN degranulation appeared to be noncompetitive. The specificity of SC-51146 for LTB4 receptors vs. fMLP receptors was improved approximately 29 and 44 times over SC-41930. SC-51146 showed relatively weak inhibitory activity on the production of superoxide, LTB4 and/or prostaglandin E2 by human PMN or HL-60 cells. SC-51146 had little activity on ram seminal vesicle cyclooxygenase, and no activity on porcine pancreatic phospholipase A2. SC-51146 is a racemate comprised of the (+) enantiomer, SC-53228, and the (-) enantiomer, SC-53229. Both stereoisomers exhibited pharmacological profiles similar to SC-51146 in these aforementioned in vitro systems. The highly potent and specific antagonistic action of SC-51146 on LTB4 receptors should be particularly useful in elucidating the role of LTB4 in the pathogenesis of inflammatory diseases where excessive levels of LTB4 have been reported.
Tsai
B S
BS
Department of Immunoinflammatory Diseases Research, Searle Research and Development, Skokie, Illinois.
Keith
R H
RH
Villani-Price
D
D
Kachur
J F
JF
Yang
D C
DC
Djuric
S W
SW
Yu
S
S
D001549:Benzamides / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015777:Eicosanoids / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010741:Phospholipases A / Q000187:drug effects; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D001549:Benzamides; D001578:Benzopyrans; D015777:Eicosanoids; D018102:Receptors, Leukotriene B4; D013481:Superoxides; C082206:7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2