RS 504393 is a selective CCR2 chemokine receptor antagonist, with IC50 values of 89nM and 100μM for human recombinant CCR2 and CCR1 receptors, respectively[1]. CCR2 is a key mediator for inflammatory monocyte activation and migration. RS 504393 can be applied for the treatment of autoimmune arthritis and cancer pain [2].
In vitro, when primary microglia were treated with RS 504393 (10μM) for 1 hour before MCP-1 stimulation, it inhibited microglial activation and reduced the expression of P2X4R in the cultured microglia [3]. Treatment of fibroblast-like synoviocytes (FLS) with RS 504393 (20μM) for 5 minutes inhibited the activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2 in CCL2 culture [4].
In vivo, RS 504393 (4mg/kg/day) was orally administered to mice with osteoarthritis (OA) for 4 weeks, which improved the changes in the cartilage and bones of the mice. RS 504393 could alleviate pain in the early stage of osteoarthritis development, but its therapeutic effect weakened in the later stage of the disease [5]. RS 504393 (4mg/kg/day, 8mg/kg/day) was administered subcutaneously once to mice with bleomycin-induced scleroderma, which reduced dermal fibrosis and dermal thickness in the mice, as well as the number of mast cells and myofibroblasts in the skin and lungs, and the amount of collagen in the skin and lungs. RS 504393 could inhibit pulmonary inflammation and fibrosis caused by bleomycin [6].
References:
[1] Mirzadegan T, et al. Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. J Biol Chem. 2000 Aug 18;275(33):25562-71.
[2] Carter P H. Progress in the discovery of CC chemokine receptor 2 antagonists, 2009–2012[J]. Expert opinion on therapeutic patents, 2013, 23(5): 549-568.
[3] Yan Y, Liang Y, Ding T, et al. PI3K/Akt signaling pathway may be involved in MCP-1-induced P2X4R expression in cultured microglia and cancer-induced bone pain rats[J]. Neuroscience letters, 2019, 701: 100-105.
[4] Nanki T, Nagasaka K, Hayashida K, et al. Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis[J]. The Journal of Immunology, 2001, 167(9): 5381-5385.
[5] Longobardi L, Temple J D, Tagliafierro L, et al. Role of the CC chemokine receptor-2 in a murine model of injury-induced osteoarthritis[J]. Osteoarthritis and cartilage, 2017, 25(6): 914-925.
[6] Ishikawa M, Yamamoto T. Antifibrogenic effects of C‐C chemokine receptor type 2 antagonist in a bleomycin‐induced scleroderma model[J]. Experimental Dermatology, 2021, 30(1): 179-184.
RS 504393是一种选择性的CCR2趋化因子受体拮抗剂，对人类重组CCR2受体和CCR1受体的IC50值分别为89nM和100μM[1]。CCR2是炎症性单核细胞激活及迁移的关键介质。RS 504393可以应用于治疗关节炎免疫发病以及癌症疼痛 [2]。
在体外，在MCP-1刺激前用RS 504393（10μM）处理小胶质细胞1小时，抑制了小胶质细胞活化并降低了培养的小胶质细胞中的P2X4R表达 [3]。用RS 504393（20μM）处理成纤维细胞样上皮细胞（FLS）5分钟，抑制了在CCL2培养下细胞外信号相关激酶1（ERK1）和ERK2的激活 [4]。
在体内，RS 504393（4mg/kg/day）通过口服治疗骨关节炎（OA）小鼠4周，改善了小鼠的骨关节软骨和骨骼的变化。RS 504393在骨关节炎发展的早期能够缓解疼痛，而在疾病后期其治疗效果减弱 [5]。RS 504393（4mg/kg/day，8mg/kg/day）通过皮下注射一次治疗博来霉素诱导的硬皮病小鼠，降低了小鼠真皮纤维化和真皮厚度，也降低了小鼠皮肤中肥大细胞和肌成纤维细胞的数量以及皮肤和肺中的胶原蛋白量。RS 504393可抑制博来霉素引发的肺部炎症和纤维化[6]。