Division of Biopharmaceutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
Sci Rep. 2017 Mar 3;7(1):52. doi: 10.1038/s41598-017-00104-z.
CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2 monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. These data render 15a a promising compound for drug development and confirms high receptor occupancy as a key parameter when targeting chemokine receptors.
CC 趋化因子受体 2（CCR2）及其内源性配体 CCL2 参与多种疾病，包括动脉粥样硬化。已经开发了几种 CCR2 拮抗剂作为潜在的治疗药物，但其体内临床疗效有限。在本报告中，我们旨在确定具有人 CCR2 长停留时间的 15a 拮抗剂是否能有效抑制小鼠疾病模型中动脉粥样硬化的发展。首先，进行放射性配体结合测定以确定 15a 对鼠 CCR2 的亲和力和结合动力学。为了评估体内疗效，用 15a 或载体（对照）每日处理给予西式饮食的载脂蛋白 E 缺乏小鼠。15a 处理可减少循环 CCR2 单核细胞的数量，并减少颈动脉和主动脉根部的粥样硬化斑块的大小。然后，我们表明 15a 的长药代动力学半衰期与高药物浓度相结合，可确保 CCR2 持续占据。这些数据表明 15a 是一种有前途的药物开发化合物，并证实高受体占有率是靶向趋化因子受体的关键参数。
