Nidufexor
(Synonyms: LMB763) 目录号 : GC34686
An FXR partial agonist
Cas No.:1773489-72-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LMB763 is a partial agonist of the farnesoid X receptor (FXR; EC50 = 7 nM).1 It is selective for FXR over a panel of enzymes, ion channels, nuclear receptors, and G protein-coupled receptors, including the androgen receptor, estrogen receptor α (ERα), and G protein-coupled bile acid receptor 1 (GPBAR1; EC50s = >30, >30, and >80 ?M, respectively). LMB763 induces expression of the FXR target genes encoding the bile salt export pump and short heterodimer partner in isolated rat hepatocytes in a concentration-dependent manner. It decreases non-alcoholic fatty liver disease (NAFLD) scores and liver fibrosis in a rat model of non-alcoholic steatohepatitis (NASH).
1.Chianelli, D., Rucker, P.V., Roland, J., et al.Nidufexor (LMB763), a novel FXR modulator for the treatment of nonalcoholic steatohepatitis (NASH)J. Med. Chem.63(8)3868-3880(2020)
| Cas No. | 1773489-72-7 | SDF | |
| 别名 | LMB763 | ||
| Canonical SMILES | CN1C(C2=CC(Cl)=CC=C2OC3)=C3C(C(N(CC4=CC=CC=C4)CC5=CC=C(C(O)=O)C=C5)=O)=N1 | ||
| 分子式 | C27H22ClN3O4 | 分子量 | 487.93 |
| 溶解度 | DMSO : 83.33 mg/mL (170.78 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0495 mL | 10.2474 mL | 20.4947 mL |
| 5 mM | 0.4099 mL | 2.0495 mL | 4.0989 mL |
| 10 mM | 0.2049 mL | 1.0247 mL | 2.0495 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis
Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.
Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH)
Introduction: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) for which therapy is suboptimal. The farnesoid-X-receptor (FXR) and the G protein bile acid receptor (GPBAR)1 are two bile acid-activated receptors that exert regulatory effects on lipid, glucose, energy, and immune homeostasis. GPBAR1 and FXR ligands have shown efficacy in reversing steatohepatitis and fibrosis in preclinical models of NASH.
Area covered: This article evaluates the efficacy and pitfalls of GPBAR1 and FXR-based therapies in the treatment of NASH. While there are no GPBAR1 agonist in clinical development, several FXR ligands have completed phase 2 and phase 3 trials in NASH. EDP305, tropifexor, cilofexor, nidufexor, TERN.101, Px-104, EYP001, MET409. Individual FXR agonists have shown variable efficacy in reversing liver steatohepatitis and fibrosis. Class-related, dose-dependent side effects: pruritus, increased plasma levels of cholesterol and LDLc, and reduction of HDL have been reported.
Expert opinion: Efficacy of FXR agonists as stand-alone therapy is limited by dose-related side effects. Efficacy of combining an FXR agonist with statins, CCR2, and ACC inhibitors is currently investigated. Identification of patient subsets would allow development of patients tailored therapy using a combination of drugs acting on different molecular mechanisms.
The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease
Introduction: The farnesoid-x-receptor (FXR) is a ubiquitously expressed nuclear receptor selectively activated by primary bile acids.
Area covered: FXR is a validated pharmacological target. Herein, the authors review preclinical and clinical data supporting the development of FXR agonists in the treatment of nonalcoholic fatty liver disease.
Expert opinion: Development of systemic FXR agonists to treat the metabolic liver disease has been proven challenging because the side effects associated with these agents including increased levels of cholesterol and LDL-c and reduced HDL-c raising concerns over their long-term cardiovascular safety. Additionally, pruritus has emerged as a common, although poorly explained, dose-related side effect with all FXR ligands, but is especially common with OCA. FXR agonists that are currently undergoing phase 2/3 trials are cilofexor, tropifexor, nidufexor and MET409. Some of these agents are currently being developed as combination therapies with other agents including cenicriviroc, a CCR2/CCR5 inhibitor, or firsocostat an acetyl CoA carboxylase inhibitor. Additional investigations are needed to evaluate the beneficial effects of combination of these agents with statins. It is expected that in the coming years, FXR agonists will be developed as a combination therapy to minimize side effects and increase likelihood of success by targeting different metabolic pathways.
Pharmacological characterization of second generation FXR agonists as effective EphA2 antagonists: A successful application of target hopping approach
It is well demonstrated the key role of Eph-ephrin system, specifically of EphA2 receptor, in supporting tumor growth, invasion, metastasis and neovascularization. We previously identified FXR agonists as eligible antagonists of Eph-ephrin system. Herein we characterize new commercially available FXR (Farnesoid X Receptor) agonists as potential Eph ligands including Cilofexor, Nidufexor, Tropifexor, Turofexorate isopropyl and Vonafexor. Our exploration based on molecular modelling investigations and binding assays shows that Cilofexor binds specifically and reversibly to EphA2 receptor with a Ki value in the low micromolar range. Furthermore, Cilofexor interferes with the phosphorylation of EphA2 and the cell retraction and rounding in PC3 prostate cancer cells, both events depending on EphA2 activation. In conclusion, we can confirm that target hopping can be a successful approach to discover new moiety of protein-protein inhibitors.