Vercirnon is a novel, orally active selective antagonist of the CCR9 chemokine receptor, with IC₅₀ values of 5.4nM and 3.4nM for inhibiting CCR9‑mediated calcium mobilization and chemotaxis in Molt‑4 cells, respectively [1-2]. By specifically blocking the binding of the ligand CCL25 to the CCR9 receptor expressed on T cells, Vercirnon inhibits the migration and recruitment of T cells to the intestinal mucosa, thereby alleviating inflammation in inflammatory bowel disease[3-4].
In vitro, treatment of SACC‑LM cells with Vercirnon (10nM) for 48 hours, Vercirnon significantly suppressed cell proliferation, migration, and invasion, while promoting apoptosis [5]. In isolated CD1 mouse islets, co‑treatment with Vercirnon (10nM) and CCL25 (50nM) for 1 hour, Vercirnon significantly enhanced glucose‑stimulated insulin secretion and increased cAMP accumulation[6].
In vivo, Vercirnon (10mg/kg or 50mg/kg) administered subcutaneously twice daily for 10 weeks in a Crohn’s disease mouse model, Vercirnon significantly improved intestinal inflammation resembling Crohn’s disease[7]. Vercirnon (50mg/kg) given subcutaneously twice daily for 20 weeks in mdr1a⁻/⁻ mice markedly ameliorated ulcerative colitis‑associated weight loss and colonic inflammation[8].
References:
[1] Vallet-Pichard A, Pol S. Grazoprevir/elbasvir combination therapy for HCV infection. Therap Adv Gastroenterol. 2017 Jan;10(1):155-167.
[2] Arseneau KO, Cominelli F. Vercirnon for the treatment of Crohn's disease. Expert Opin Investig Drugs. 2013 Jul;22(7):907-13.
[3] Haberer LJ, McSherry I, Cargill A, et al. Effects of vercirnon on the activity of CYP3A4, CYP2C19 and CYP2C8 enzymes and BCRP and OATP1B1 transporters using probe substrates. Eur J Clin Pharmacol. 2014 Jan;70(1):37-45.
[4] Zhang J, Romero J, Chan A, et al. Biarylsulfonamide CCR9 inhibitors for inflammatory bowel disease. Bioorg Med Chem Lett. 2015 Sep 1;25(17):3661-4.
[5] Chai S, Wen Z, Zhang R, et al. CCL25/CCR9 interaction promotes the malignant behavior of salivary adenoid cystic carcinoma via the PI3K/AKT signaling pathway. PeerJ. 2022 Aug 19;10:e13844.
[6] Atanes P, Lee V, Huang GC, et al. The role of the CCL25-CCR9 axis in beta-cell function: potential for therapeutic intervention in type 2 diabetes. Metabolism. 2020 Dec;113:154394.
[7] Walters MJ, Wang Y, Lai N, et al. Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease. J Pharmacol Exp Ther. 2010 Oct;335(1):61-9.
[8] Bekker P, Ebsworth K, Walters MJ, et al. CCR9 Antagonists in the Treatment of Ulcerative Colitis. Mediators Inflamm. 2015;2015:628340.
Vercirnon是一种新型的、具有口服活性的CCR9趋化因子受体选择性拮抗剂，抑制CCR9介导的Molt-4细胞钙离子动员和趋化作用的IC₅₀值分别为5.4nM和3.4nM[1-2]。Vercirnon通过特异性阻断配体CCL25与表达在T细胞表面的受体CCR9结合，从而抑制T细胞向小肠黏膜的迁移和募集，可缓解炎症性肠病的炎症[3-4]。
在体外，Vercirnon（10nM）处理SACC-LM细胞48小时，Vercirnon显著抑制细胞增殖、迁移和侵袭能力，同时促进细胞凋亡[5]。Vercirnon（10nM）与CCL25（50nM）联合处理离体CD1小鼠胰岛1小时，Vercirnon显著诱导葡萄糖刺激胰岛素分泌，并促进cAMP的积累 [6]。
在体内，Vercirnon（10mg/kg或50mg/kg）每日两次皮下注射处理克罗恩病小鼠，连续10周。Vercirnon显著改善了与克罗恩病类似的肠道炎症[7]。Vercirnon（50mg/kg）每日两次皮下注射，用于处理mdr1a⁻/⁻小鼠，连续20周。Vercirnon显著改善了溃疡性结肠炎相关的体重减轻和结肠炎症[8]。