CP-105696 (Pfizer 105696) is a structurally novel, effective and selective leukotriene B4 (LTB4) receptor antagonist with an IC50 of 8.42nM[1]. LTB4 is a leukotriene substance related to inflammatory responses, which can induce the formation of reactive oxygen species and the release of enzymes in lysosomes[2]. CP-105696 antagonizes the effects of LTB4 or LTB4 receptor ligands and may inhibit the important inflammatory circuits in the early post-transplantation period[3,4].
In vitro, human neutrophils were treated with CP-105696 (0.3nM), which significantly inhibited the binding of [3H]LTB4 to the high-affinity LTB4 receptor of human neutrophils, with an lC50 value of 8.42±0.26nM. CP-105696 inhibited LTB4 (5nM) -mediated human neutrophil chemotaxis in a non-competitive manner, with an IC50 value of 5.0±2nM[1]. CP-105696 inhibits LTB4-mediated chemotaxis of monkey neutrophils and suppresses the recruitment of neutrophils to the inflammatory site[2].
In vivo, CP-105696 (10, 50, 100mg/kg) was orally administered by gavage in mice that underwent ectopic heart transplantation. After 28 days of treatment, the expression of CD11 anti-anisinin family members (CD11b) in the non-lymphocytic cell population of infiltrating cells in the transplanted heart decreased, reducing the inflammatory response of isolin resistance in immune rejection[3].
References:
[1]Showell HJ, Pettipher ER, Cheng JB, Breslow R, Conklyn MJ, Farrell CA, Hingorani GP, Salter ED, Hackman BC, Wimberly DJ, et al. The in vitro and in vivo pharmacologic activity of the potent and selective leukotriene B4 receptor antagonist CP-105696. J Pharmacol Exp Ther. 1995 Apr;273(1):176-84. PMID: 7714764.
[2]Turner CR, Breslow R, Conklyn MJ, Andresen CJ, Patterson DK, Lopez-Anaya A, Owens B, Lee P, Watson JW, Showell HJ. In vitro and in vivo effects of leukotriene B4 antagonism in a primate model of asthma. J Clin Invest. 1996 Jan 15;97(2):381-7.
[3]Weringer EJ, Perry BD, Sawyer PS, Gilman SC, Showell HJ. Antagonizing leukotriene B4 receptors delays cardiac allograft rejection in mice. Transplantation. 1999 Mar 27;67(6):808-15.
[4]Corry RJ, Winn HJ, Russell PS. Primarily vascularized allografts of hearts in mice. The role of H-2D, H-2K, and non-H-2 antigens in rejection. Transplantation. 1973 Oct;16(4):343-50.
CP-105696 (Pfizer 105696)是一种结构新颖、有效并具有选择性的白三烯B4（LTB4）受体拮抗剂，IC50为8.42nM[1]。LTB4是一种与炎症反应有关的白三烯类物质，够诱导形成活性氧和溶酶体中酶的释放[2]。CP-105696拮抗LTB4或LTB4受体配体的作用，可能抑制移植后早期重要炎症回路[3,4]。
在体外，CP-105696（0.3 nM）处理人中性粒细胞，显著抑制[3H]LTB4与人中性粒细胞高亲和力LTB4受体结合，IC50值为8.42±0.26nM。CP-105696以非竞争性方式抑制LTB4（5nM）介导的人中性粒细胞趋化性，IC50值为 5.0±2nM[1]。CP-105696抑制LTB4介导的猴中性粒细胞趋化性，抑制中性粒细胞募集到炎症部位[2]。
在体内，CP-105696（10、50、100mg/kg）口服灌胃给药于接受异位心脏移植手术的小鼠，治疗28天后，移植心脏中浸润细胞中的非淋巴细胞群中的CD11抗原样家族成员（CD11b）表达减少，降低免疫排斥中的炎症反应岛素抵抗[3]。