CP-105,696

CP-105696 is a structurally novel, selective and potent LTB ₄ receptor antagonist. In vitro, CP-105696 inhibits [ ³ H]LTB ₄ (0.3 nM) binding to high-affinity LTB ₄ receptors on human neutrophils with an lC ₅₀ value of 8.42±0.26 nM. Scatchard analyses of [ ³ H]LTB ₄ binding to these high-affinity receptors indicate that CP-105696 acts as a noncompetitive antagonist. CP-105696 inhibits human neutrophil chemotaxis mediated by LTB ₄ (5 nM) in a noncompetitive manner with an IC ₅₀ value of 5.0±2.0 nM. Scatchard analyses of [ ³ H]LTB ₄ binding to low-affinity receptors on neutrophils indicate that CP-105696 acts as a competitive antagonist at this receptor, and inhibition of LTB ₄ -mediated CD11b upregulation on human neutrophils is competitively inhibited by CP-105696 (pA ₂ =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, LTB ₄ (5 nM)-mediated Ca ²⁺ mobilization is inhibited by CP-105696 with an lC ₅₀ value of 940±70 nM.

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.