Abstract

CP-195543 [(+)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid] is a structurally novel, selective and potent leukotriene B₄ (LTB₄) receptor antagonist. In vitro CP-195543 inhibited [³H]LTB₄binding to high-affinity LTB₄ receptors on human neutrophils (HN) and murine spleen membranes with IC₅₀values of 6.8 nM (K_i = 4.9 nM) and 37.0 nM (K_i = 26.9 nM), respectively. CP-195543 inhibited human and mouse neutrophil chemotaxis mediated by LTB₄ with IC₅₀ values of 2.4 nM and 7.5 nM, respectively. Evidence of noncompetitive antagonist effects on the HN high-affinity LTB₄ receptor was obtained by Scatchard analysis of [³H]LTB₄ binding to and chemotaxis of HN to LTB₄. Scatchard analyses of [³H]LTB₄ binding to low-affinity receptors on HN indicated that CP-195543 acted as a competitive antagonist at this receptor, and inhibition of LTB₄-mediated CD11b up-regulation on HN was inhibited competitively by CP-195543 (pA₂ = 7.66). In whole blood, CP-195543 also blocked CD11b up-regulation on HN (pA₂ = 7.12) and murine neutrophils (pA₂ = 7.06) with a similar potency. LTB₄-mediated CD11b up-regulation on human monocytes and eosinophils in whole blood were inhibited by CP-195543 with IC₅₀ values of 270 nM and 420 nM, respectively. CP-195543 at 10 μM failed to inhibit HN chemotaxis and CD11b up-regulation mediated through alternative (i.e., complement fragment 5a, interleukin-8, platelet-activating factor) G-protein-coupled chemotactic factor receptors. In vivo, after oral administration, CP-195543 blocked LTB₄-mediated neutrophil infiltration in guinea pig and murine skin with ED₅₀ values of 0.1 mg/kg and 2.8 mg/kg p.o., respectively. When administered in osmotic pumps, CP-195543 reduced the clinical symptoms and attendant weight loss in an IL-1-exacerbated murine model of collagen-induced arthritis with half-maximal effects associated with plasma drug levels of 0.4 to 0.5 μg/ml. Collectively these data provide evidence of thein vitro potency and in vivo efficacy of a novel LTB₄ antagonist and support its clinical evaluation in a variety of inflammatory diseases in man.