GW4064

GW4064, as a synthetic FXR agonist, was used for treatment of cholestatic liver diseases, metabolic syndrome and alcoholic liver disease.^[1]

In vitro experiment it shown that the IC50 values of GW4064 in SW620 and HT-29 cells were 7.6 μM and 13.8 μM, respectively.^[2] In vitro efficacy test it indicated that the GW4064 response was concentration dependent (EC50 values after 24 hours of treatment were 0.012 μM and 0.015 μM, respectively) on CRE and NFAT-RE luciferases.^[3] GW4064 dose dependently enhanced the basal cAMP level with EC50 of 0.241 μM, and suppressed forskolin-induced cAMP accumulation with IC50 of 0.07 μM.^[3]

In vivo study it demonstrated that Rats in the treatment group received an interperitoneal GW4064 injection of 30 mg/kg every other day for 2 wk, GW4064 could correct BA dysmetabolism to alleviate hepatotoxicity in SBR animals. In the meanwhile, GW4064 intervention decreased the fecal bile excretion and elevated plasma/hepatic conjugated BA levels. It also increased the reabsorption of conjugated BAs by inducing apical sodium-dependent bile salt transporter expression in the ileum.^[4] In vivo, treatment with 30 mg/kg for 7 consecutive days intraperitoneally, GW4064 alleviated social deficits in BTBR mice and modulated selective aspects of the composition of the gut microbiota.^[5] Mice were injected 20 mg/kg GW4064 intraperitoneally result in that decreased hepatic inflammation in the LPS-induced murine liver injury model.^[6].

References:
[1]. A.S. Alawad, C. Levy. FXR agonists: from bench to bedside, a guide for clinicians Dig. Dis. Sci., 61 (12) (2016), pp. 3395-3404.
[2]. Guo J, et al. GW4064 enhances the chemosensitivity of colorectal cancer to oxaliplatin by inducing pyroptosis. Biochem Biophys Res Commun. 2021 Apr 9;548:60-66.
[3]. Singh N, et al. Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors. Mol Endocrinol. 2014 May;28(5):659-73.
[4]. Cao Y, et al. FXR agonist GW4064 improves liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection. Am J Physiol Gastrointest Liver Physiol. 2019 Aug 1;317(2):G108-G115.
[5]. Liu J, et al. GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice. Front Cell Infect Microbiol. 2022 Jun 22;12:911259.
[6]. Liu HM, et al. GW4064 attenuates lipopolysaccharide induced hepatic inflammation and apoptosis through inhibition of the Toll like receptor 4 mediated p38 mitogen activated protein kinase signaling pathway in mice. Int J Mol Med. 2018 Mar;41(3):1455-1462.

GW4064作为合成的FXR激动剂，用于治疗胆汁淤积性肝病、代谢综合征和酒精性肝病。^[1]

体外实验表明GW4064在SW620和HT-29细胞中的IC50值分别为7.6 μM和13.8 μM。^[2] 体外药效试验表明GW4064反应对 CRE 和 NFAT-RE 荧光素酶具有浓度依赖性（处理 24 小时后 EC50 值分别为 0.012 μM 和 0.015 μM）。^[3] GW4064 剂量依赖性地增强基础 cAMP 水平，EC50 为 0.241 μM，并抑制毛喉素诱导的 cAMP 积累，IC50 为 0.07 μM。^[3]

体内研究表明，治疗组的大鼠每隔一天接受 30 mg/kg 的 GW4064 腹腔注射，持续 2 周，GW4064 可以纠正 BA 代谢障碍，减轻 SBR 动物的肝毒性。同时，GW4064 干预减少了粪便胆汁排泄并升高了血浆/肝脏结合 BA 水平。它还通过在回肠中诱导顶端钠依赖性胆盐转运蛋白表达来增加结合 BA 的重吸收。^[4] 在体内，连续 7 天腹膜内注射 30 mg/kg，GW4064 减轻了社会BTBR 小鼠的缺陷和调节肠道微生物群组成的选择性方面。^[5] 小鼠腹膜内注射 20 mg/kg GW4064 导致 LPS 诱导的小鼠肝损伤模型中的肝脏炎症减少.^[6].