CCR2 antagonist 1 is a high-affinity and long-residence-time chemokine receptor 2 antagonist with the Ki value of 2.4nM [1]. CCR2 antagonist 1 has been widely used in animal models to target the CCL2-CCR2 axis and prevent the occurrence of atherosclerosis[2]. CCR2 antagonist 1 can be used as a model compound to investigate the relationship between the kinetic stability of the drug target complex and the water-screening hydrogen bonds[3].
In vivo, CCR2 antagonist 1 treatment via intraperitoneal injection at a dose of 5mg/kg/day for 4 weeks significantly reduced atherosclerotic plaque development in the carotid artery at the site of maximal stenosis in apoE−/− mice[4]. Continuous intraperitoneal injection of 30mg/kg dose of CCR2 antagonist 1 for 14 consecutive days could significantly reduce brain metastasis in the E0771-BrM breast cancer mouse model[5].
References:
[1] Vilums M, Zweemer A J M, Barmare F, et al. When structure–affinity relationships meet structure–kinetics relationships: 3-((Inden-1-yl) amino)-1-isopropyl-cyclopentane-1-carboxamides as CCR2 antagonists[J]. European journal of medicinal chemistry, 2015, 93: 121-134.
[2] Bot I, Ortiz Zacarias N V, de Vries H, et al. Longer Receptor Residence Times Improve the Effectiveness of CCR2 Antagonists in the Prevention of Atherosclerosis[J]. Circulation, 2015, 132(suppl_3): A11581-A11581.
[3] Magarkar A, Schnapp G, Apel A K, et al. Enhancing drug residence time by shielding of intra-protein hydrogen bonds: a case study on CCR2 antagonists[J]. ACS medicinal chemistry letters, 2019, 10(3): 324-328.
[4] Bot I, Ortiz Zacarías N V, de Witte W E A, et al. A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy[J]. Scientific reports, 2017, 7(1): 52.
[5] Ma W, Oliveira-Nunes M C, Xu K, et al. Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment[J]. Nature communications, 2023, 14(1): 2632.
CCR2 antagonist 1是一种具有高亲和力及长停留时间特性的趋化因子受体2拮抗剂，Ki值为2.4nM[1]。CCR2 antagonist 1已广泛用于动物模型中以靶向CCL2-CCR2轴，从而预防动脉粥样硬化的发生[2]。CCR2 antagonist 11可作为模型化合物，用于研究药物-靶点复合物的动力学稳定性与水屏蔽氢键之间的关系[3]。
在体内，通过腹腔注射给予CCR2 antagonist 1（5mg/kg/day；持续4周），能显著减轻apoE−/−小鼠颈动脉最大狭窄部位的动脉粥样硬化斑块发展[4]。在E0771-BrM乳腺癌小鼠模型中，连续14天腹腔注射30mg/kg剂量的CCR2 antagonist 1可显著减少脑转移的发生[5]。