Vorapaxar

Vorapaxar is an orally active, selective, and competitive antagonist of the thrombin receptor protease-activated receptor (PAR-1), with a K_d value of 1.27 ± 0.3nM. Its K_i value increases as plasma concentration rises, reaching 39.2nM at 100% plasma.^[1]. Vorapaxar has shown anti-fibrotic and anti-cancer potential^[2][3]. The anti-platelet properties of Vorapaxar further contribute to its efficacy in preventing thrombosis and improving outcomes in patients with cardiovascular conditions^[1][4][5].

In vitro, Vorapaxar treatment (0.2, 0.5 and 1μM) on mouse lung fibroblasts (MLG cells) and human lung fibroblasts (HFL1 cells) for 24h inhibited the migration of thrombin-activated fibroblasts and reduced the expression of fibroblast activation markers α-SMA, collagen I and fibronectin proteins in a dose-dependent manner by weakening the binding of HSP90β and TGF beta receptor type II and inhibiting TGF-β-mediated Smad2/3 phosphorylation^[2]. Preincubation of three epithelial ovarian cancer cell lines (SKOV-3, OVCAR-3 and CaOV-3) with Vorapaxar (5nM) for 1h reduced thrombin induced cellular proliferation back to basal levels. These results provides a basis for the potential application of Vorapaxar in the treatment of ovarian cancer^[3].

In vivo, Vorapaxar (30μg/kg) was administrated into Doxorubicin-induced cardiac injury mice model via oral gavage daily for 5 days. The results showed that Vorapaxar improved the heart function of WT mice to levels seen in PAR-1^−/− mice after Doxorubicin injection. This suggests that Vorapaxar could reduce the cardiotoxic effects of Doxorubicin in patients^[5]. The hepatic ischemia-reperfusion injury (IRI) mice model received intraperitoneal administration of 5mg/kg of Vorapaxar. Vorapaxar treatment exerted antiapoptotic effect and ameliorated hepatocellular injury by attenuating activation of caspase9 and markedly inducing phosphorylation of both AKT and ERK 1/2^[6].Vorapaxar (1.75mg/kg) administered orally twice a week into streptozotocin-induced diabetic mice model for 20 weeks prevented mice developing significant albuminuria, mesangial expansion and glomerular fibronectin deposition. The results showed that PAR-1 inhibition by Vorapaxar prevented the development of diabetic nephropathy^[7].

References:
[1] Hawes B E, Zhai Y, Hesk D, et al.In vitro pharmacological characterization of vorapaxar, a novel platelet thrombin receptor antagonist. Eur J Pharmacol. 2015 Sep 5:762:221-8.
[2] Xiao T, Ren S F, Bao J L, et al. Vorapaxar proven to be a promising candidate for pulmonary fibrosis by intervening in the PAR1/JAK2/STAT1/3 signaling pathway-an experimental in vitro and vivo study. Eur J Pharmacol. 2023 Mar 15:943:175438.
[3] Chanakira A, Westmark P R, Ong I M, Sheehan J P. Tissue factor-factor VIIa complex triggers protease activated receptor 2-dependent growth factor release and migration in ovarian cancer.Gynecol Oncol. 2017 Apr;145(1):167-175.
[4] Leonardi S, Tricoci P, Becker R C. Protease-activated receptor-1 inhibitors: a novel class of antiplatelet agents for the treatment of patients with acute coronary syndrome. Adv Cardiol. 2012:47:87-99.
[5] Antoniak S, Tatsumi K, Schmedes C M, et al. Protease-activated receptor 1 activation enhances doxorubicin-induced cardiotoxicity. J Mol Cell Cardiol. 2018 Sep:122:80-87.
[6] Noguchi D, Kuriyama N, Ito T, et al. Antiapoptotic Effect by PAR-1 Antagonist Protects Mouse Liver Against Ischemia-Reperfusion Injury.J Surg Res. 2020 Feb:246:568-583.
[7] Waasdorp M, Duitman J, Florquin S, Spek C A. Vorapaxar treatment reduces mesangial expansion in streptozotocin-induced diabetic nephropathy in mice. Oncotarget. 2018 Apr 24;9(31):21655-21662.

Vorapaxar是一种具有口服活性、选择性和竞争性的凝血酶受体蛋白酶激活受体 (PAR-1) 拮抗剂，K_d值为1.27±0.3nM，K_i值随血浆浓度升高而升高，100%血浆时达到39.2nM^[1]。Vorapaxar显示出抗纤维化和抗癌的潜力^[2][3]。Vorapaxar的抗血小板特性进一步有助于其在预防血栓形成和改善心血管疾病患者预后方面的有效性^[1][4][5]。

在体外实验中，Vorapaxar（0.2、0.5和1μM）处理小鼠肺成纤维细胞（MLG细胞）和人肺成纤维细胞（HFL1细胞）24小时，能够以剂量依赖的方式抑制凝血酶激活的成纤维细胞迁移，并通过减弱HSP90β与TGF-β受体II的结合以及抑制TGF-β介导的Smad2/3磷酸化，降低成纤维细胞激活标志物α-SMA、胶原蛋白I和纤维连接蛋白的表达^[2]。将三种上皮性卵巢癌细胞系（SKOV-3、OVCAR-3和CaOV-3）预先用5nM的Vorapaxar处理1小时，可降低凝血酶诱导的癌细胞增殖。这些结果为Vorapaxar在卵巢癌治疗中的潜在应用提供了依据^[3]。

在体内实验中，Vorapaxar（30μg/kg）通过口服灌胃的方式每日给药一次，连续给药5天，治疗Doxorubicin诱导的心脏损伤小鼠模型，结果显示Vorapaxar可在Doxorubicin注射后将野生型（WT）小鼠的心脏功能改善至与PAR-1基因敲除（PAR-1−/−）小鼠的水平相当。这表明Vorapaxar能够减轻Doxorubicin对患者的心脏毒性^[5]。在肝脏缺血再灌注损伤（IRI）小鼠模型中，通过腹腔注射给予5mg/kg的Vorapaxar，Vorapaxar治疗发挥了抗凋亡作用，通过减轻caspase9的激活以及显著诱导AKT和ERK 1/2的磷酸化，减轻了肝细胞损伤^[6]。在链脲佐菌素诱导的糖尿病小鼠模型中，Vorapaxar（1.75mg/kg）每周口服给药两次，连续给药20周，可防止小鼠出现显著的蛋白尿、系膜扩张和肾小球纤维连接蛋白沉积。结果表明，Vorapaxar通过抑制PAR-1可预防糖尿病肾病的发展^[7]。