CP-105696

CP-105696 is a potent and selective Leukotriene B₄ Receptor antagonist, with an IC₅₀ of 8.42 nM. IC50 & Target: IC50: 8.42 nM (LTB₄)^[1]. In Vitro: CP-105696 is a structurally novel, selective and potent LTB₄ receptor antagonist. In vitro, CP-105696 inhibits [³H]LTB₄ (0.3 nM) binding to high-affinity LTB₄ receptors on human neutrophils with an lC₅₀ value of 8.42±0.26 nM. Scatchard analyses of [³H]LTB₄ binding to these high-affinity receptors indicate that CP-105696 acts as a noncompetitive antagonist. CP-105696 inhibits human neutrophil chemotaxis mediated by LTB₄ (5 nM) in a noncompetitive manner with an IC₅₀ value of 5.0±2.0 nM. Scatchard analyses of [³H]LTB₄ binding to low-affinity receptors on neutrophils indicate that CP-105696 acts as a competitive antagonist at this receptor, and inhibition of LTB₄-mediated CD11b upregulation on human neutrophils is competitively inhibited by CP-105696 (pA₂=8.03±0.19). CP-105696 at 10 μM does not inhibit either human neutrophil chemotaxis or CD11b upregulation mediated through alternate (i.e., C5a, lL-8, PAF) G-protein coupled chemotactic factor receptors. In isolated human monocytes, LTB₄ (5 nM)-mediated Ca²⁺ mobilization is inhibited by CP-105696 with an lC₅₀ value of 940±70 nM^[1]. In Vivo: At a dose of 50 mg/kg/day (28 days), B10.BR (H2k) allografts transplanted into C57Bl/6 (H2b) recipients are significantly protected, as reflected by the mean survival time versus control grafts (27±20 days [n=10] vs. 12±6 days [n=14]; P=0.0146). Using an induction protocol (day -1 to day 3), CP-105696 at 100 mg/kg/day significantly prolongs allograft survival (33±23 days [n=9]; P=0.0026), but CP-105696 at 10 mg/kg/day does not (18±16 days [n=8]; P=0.1433). Syngeneic grafts survive indefinitely (n=11). Immunohistological evaluation of allografts at rejection reveals a mononuclear cell infiltrate composed primarily of CD3+ and CD11b+ (Mac-1+) cells, which are infrequent in syngeneic grafts. Allografts from mice treated with CP-105696 at 50 or 100 mg/kg/day demonstrat a selective reduction in β2-integrin (Mac-1) expression on monocytes/macrophages, as demonstrated by CD11b staining density compared with allograft controls^[2].