Vol. 288, Issue 1, 286-294, January 1999

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

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana

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]LTB₄ binding 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 by N-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 K_i 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 with N-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.