CP-105696 is a potent and selective leukotriene B4 (LTB4) receptor antagonist for the study of allograft rejection.

LTB4:8.42±0.26 nM

CP-105696 is a structurally novel, selective, and potent LTB4 receptor antagonist. In vitro, it inhibits [3H]LTB4 (0.3 nM) binding to high-affinity LTB4 receptors on human neutrophils with an IC50 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.In a noncompetitive manner, CP-105696 inhibits human neutrophil chemotaxis mediated by LTB4 (5 nM) 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. Furthermore, CP-105696 competitively inhibits LTB4-mediated CD11b upregulation on human neutrophils (pA2=8.03±0.19).At 10 μM, CP-105696 does not inhibit either human neutrophil chemotaxis or CD11b upregulation mediated through alternate G-protein coupled chemotactic factor receptors (i.e., C5a, IL-8, PAF). In isolated human monocytes, CP-105696 inhibits LTB4 (5 nM)-mediated Ca2+ mobilization with an IC50 value of 940±70 nM[2].

At a dose of 50 mg/kg/day (for 28 days), B10.BR (H2k) allografts transplanted into C57Bl/6 (H2b) recipients show significant protection, as evidenced by the mean survival time compared to control grafts (27±20 days [n=10] vs. 12±6 days [n=14]; P=0.0146). Utilizing 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), while CP-105696 at 10 mg/kg/day does not (18±16 days [n=8]; P=0.1433). Syngeneic grafts exhibit indefinite survival (n=11).Immunohistological evaluation of allografts at rejection reveals a mononuclear cell infiltrate primarily composed 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 demonstrate a selective reduction in β2-integrin (Mac-1) expression on monocytes/macrophages, as indicated by CD11b staining density compared with allograft controls[1].