THE IN-VITRO AND IN-VIVO PHARMACOLOGICAL ACTIVITY OF THE POTENT AND SELECTIVE LEUKOTRIENE B-4 RECEPTOR ANTAGONIST CP-105696

CP-105696, phenyl-benzyl)-4-hydroxy-chroman-7-yl]cyclopentane carboxyl ic acid, is a structurally novel, selective and potent leukotriene B-4 (LTB(4)) receptor antagonist. In vitro, CP-105696 inhibited [H-3]LTB( 4) (0.3 nM) binding to high-affinity LTB(4) receptors on human neutrop hils with an IC50 value of 8.42 +/- 0.26 nM. Scatchard analyses of [H- 3]LTB(4) binding to these high-affinity receptors indicated that CP-10 5696 acted as a noncompetitive antagonist. CP-105696 inhibited human n eutrophil chemotaxis mediated by LTB(4) (5 nM) in a noncompetitive man ner with an IC50 value of 5.0 +/- 2.0 nM. Scatchard analyses of [H-3]L TB(4) binding to low-affinity receptors on neutrophils indicated that CP-105696 acted as a competitive antagonist at this receptor, and inhi bition of LTB(4)-mediated CD11b upregulation on human neutrophils was competitively inhibited by CP-105696 (pA(2) = 8.03 +/- 0.19). CP-10569 6 at 10 mu M did not inhibit either human neutrophil chemotaxis or CD1 1b upregulation mediated through alternate (i.e., C5a, IL-8, PAF) G-pr otein coupled chemotactic factor receptors. In isolated human monocyte s, LTB(4) (5 nM)-mediated Ca++ mobilization was inhibited by CP-105696 with an IC50 value of 940 +/- 70 nM. In vivo, after oral administrati on, CP-105696 blocked neutrophil and eosinophil infiltration in cavine dermis mediated by either LTB(4) or arachidonic acid with ED(50) valu es of 0.3 +/- 0.1 mg/kg. 12(R)-Hydroxyeicosatetraenoic acid-mediated n eutrophil infiltration was blacked by 76.4 +/- 14.8% at 3 mg/kg. This evidence of its potent and selective in vitro and in vivo LTB(4) antag onist properties suggests that CP-105696 may have clinical utility in the treatment of various inflammatory diseases in the human where eith er LTB(4) or other potential agonists acting at this receptor are invo lved.