Pharmacologic Actions of the Second-Generation Leukotriene B4 Receptor Antagonist LY293111: In Vitro Studies
- William T. Jackson,
- Larry L. Froelich,
- Robert J. Boyd,
- James P. Schrementi,
- David L. Saussy, Jr.1,
- Richard M. Schultz,
- J. Scott Sawyer,
- Michael J. Sofia2,
- David K. Herron,
- Theodore Goodson, Jr.,
- David W. Snyder,
- Penni A. Pechous,
- Stephen M. Spaethe,
- Carlos R. Roman and
- Jerome H. Fleisch
Abstract
The in vitro actions were investigated of LY293111, a potent and selective leukotriene B4 (LTB4) receptor antagonist, on human neutrophils, human blood fractions, guinea pig lung membranes, and guinea pig parenchymal and tracheal strips. The IC50 for inhibiting [3H]LTB4binding to human neutrophils was 17.6 ± 4.8 nM. LY293111 inhibited LTB4-induced human neutrophil aggregation (IC50 = 32 ± 5 nM), luminol-dependent chemiluminescence (IC50 = 20 ± 2 nM), chemotaxis (IC50 = 6.3 ± 1.7 nM), and superoxide production by adherent cells (IC50 = 0.5 nM). Corresponding responses induced byN-formyl-l-methionyl-l-leucyl-l-phenylalanine were inhibited by 100-fold higher concentrations of LY293111. LTB4 binding to guinea pig tissues and subsequent activation were also inhibited. The Ki for inhibition of [3H]LTB4 binding to lung membranes was 7.1 ± 0.8 nM; IC50 for preventing binding of [3H]LTB4 to spleen membranes was 65 nM. The compound inhibited LTB4-induced contraction of guinea pig lung parenchyma. At 10 nM, LY293111 caused a parallel rightward shift of the LTB4 concentration-response curve. At higher concentrations, plots were shifted in a nonparallel manner, and maximum responses were depressed. LY293111 did not prevent antigen-stimulated contraction of sensitized trachea strips. At micromolar concentrations, LY293111 inhibited production of LTB4 and thromboxane B2 by plasma-depleted human blood stimulated withN-formyl-l-methionyl-l-leucyl-l-phenylalanine and thrombin. In addition, at these higher concentrations, formation of LTB4 by A23187-activated whole blood and conversion of arachidonic acid to LTB4 by a human neutrophil cytosolic fraction were inhibited. In summary, LY293111 is a second-generation LTB4 receptor antagonist with much improved potency in a variety of functional assay systems.
Footnotes
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Send reprint requests to: Dr. William T. Jackson, Cardiovascular Research, MC-304, Drop Code 0524, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285. E-mail:wtj{at}lilly.com.
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↵1 Present address: Glaxo Research Institute, Research Triangle Park, NC 27709.
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↵2 Present address: Intercardia Research Laboratories, 8 Cedar Brook Dr., Cranbury, NJ 08512.
- Abbreviations:
- LTB4
- leukotriene B4
- A23187
- 6S-[6α(2S*,3S*),8β(R*),9β,11α]5-(methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2(1H-pyrrol-2-yl)ethyl]1,7-dioxaspirol[5.5]undec-2-yl]methyl]4-benzoxazolecarboxylic acid
- BES
- N,N-bis[2-hydroxyethyl]2-aminoethanesulfonic acid
- DMSO
- dimethylsulfoxide
- EDTA
- ethylenediaminetetraacetic acid
- fMLP
- N-formyl-l-methionyl-l-leucyl-l-phenylalanine
- [3H]LTB4
- [5,6,8,9,11,12,14,15(n)-3H]leukotriene B4
- LTD4
- leukotriene D4
- LY255283
- 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]ethanone
- LY293111
- 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy]propoxy]phenoxy]benzoic acid
- PIPES
- piperazine-N,N′-bis[2-ethanesulfonic acid]
- SC-41930
- 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid
- TxA2
- thromboxane A2
- TxB2
- thromboxane B2
- U46619
- 15(S)-hydroxy-11α,9α-(epoxymethano)prosta-5Z,13E-dienoic acid
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- Received May 13, 1998.
- Accepted August 17, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
