CP-105696 is a potent and selective leukotriene B4 (LTB4) receptor antagonist used to study 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 of 8.42±0.26 nM and acts as a noncompetitive antagonist. It noncompetitively inhibits LTB4 (5 nM)-mediated human neutrophil chemotaxis with an IC50 of 5.0±2.0 nM. For low-affinity receptors on neutrophils, CP-105696 acts as a competitive antagonist according to Scatchard analyses. Additionally, it competitively inhibits LTB4-mediated CD11b upregulation on human neutrophils (pA2=8.03±0.19). At 10 μM, CP-105696 does not inhibit human neutrophil chemotaxis or CD11b upregulation mediated by other G-protein coupled receptors (e.g., C5a, IL-8, PAF). In isolated human monocytes, it inhibits LTB4 (5 nM)-mediated Ca2+ mobilization with an IC50 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, with mean survival time of 27±20 days (n=10) compared to control grafts' 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 to 33±23 days (n=9; P=0.0026), whereas at 10 mg/kg/day, it 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 show a selective reduction in β2-integrin (Mac-1) expression on monocytes/macrophages, as indicated by CD11b staining density compared with allograft controls[1].