| 规格 | 价格 | 库存 | 数量 |
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| 靶点 |
At 94 nM, ML-290 is a powerful agonist of the relaxin/insulin-like family peptide receptor (RXFP1) and an anti-fibrotic gene activator, making it the first of its kind in the field[1]. After 24 and 72 hours of activation, human hepatic stellate cells that have been exposed to ML290 (5 μM) exhibit relaxin-like, anti-fibrotic gene expression [1].
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| 体外研究 (In Vitro) |
ML-290 浓度为 94 nM，是松弛素/胰岛素样家族肽受体 (RXFP1) 的强效激动剂和抗纤维化基因激活剂，使其成为该领域的首个此类药物[1]。激活 24 小时和 72 小时后，暴露于 ML290 (5 μM) 的人肝星状细胞表现出松弛素样抗纤维化基因表达 [1]。
ML-290 (化合物65) 是一种强效、选择性的人RXFP1受体小分子激动剂。在使用转染了人RXFP1的HEK293细胞进行的cAMP功能实验中，ML-290的EC₅₀为0.094 µM，相对于福斯高林的最大效能为98%。它对相关的RXFP2受体和AVPR1B受体具有选择性。 [1] 在通过塑料培养皿培养以诱导活化的原代人肝星状细胞中，用5 µM ML-290处理24和72小时，可诱导出具有松弛素抗纤维化特征基因表达谱。这包括显著下调促纤维化基因（ACTA2、TGFB1、CTGF）以及上调基质金属蛋白酶1（MMP1）和过氧化物酶体增殖物激活受体γ（PPARG）。 [1] |
| 体内研究 (In Vivo) |
在雄性C57/BL6小鼠中评估了ML-290的药代动力学特征。静脉注射（3 mg/kg）后，其血浆半衰期为6.6小时，表观分布容积较高（24.5 L/kg），表明组织渗透性良好。静脉给药后，心脏组织中的药物暴露量约为血浆暴露量的6倍。口服给药（30 mg/kg）后，血浆半衰期为5.5小时，生物利用度为14%。 [1]
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| 细胞实验 |
cAMP检测实验： 通过测量cAMP水平来评估RXFP1的激活。用稳定或瞬时转染了人RXFP1、RXFP2或AVPR1B受体的HEK293细胞（或THP1细胞），在37°C、5% CO₂条件下，用松弛素、测试化合物或福斯高林刺激30分钟。使用均相时间分辨荧光检测试剂盒定量细胞内的cAMP。在兼容的酶标仪上读取信号。生成浓度-反应曲线，并通过非线性回归分析确定EC₅₀值。 [1]
肝星状细胞基因表达调控实验： 将原代人肝星状细胞接种于多聚赖氨酸包被的培养皿中，并在特定生长培养基中培养。将细胞分为三组，分别用溶解于DMSO的5 µM ML-290 或单独的DMSO溶剂（对照）处理24或72小时。提取总RNA并合成cDNA。使用基因特异性引物和预混液进行定量PCR。基因表达水平以GAPDH归一化，并使用比较Ct法计算相对倍数变化。使用Student's t检验确定统计学显著性。 [1] |
| 动物实验 |
Pharmacokinetic Study in Mice: Male C57/BL6 mice were administered ML-290 via intravenous injection (3 mg/kg) or oral gavage (30 mg/kg). For the IV study, the compound was formulated in a suitable vehicle (details of formulation not specified in the main text). Blood samples were collected at various time points post-dose to obtain plasma. In a separate experiment, heart tissues were also collected after IV and oral dosing. Drug concentrations in plasma and heart homogenates were determined to calculate pharmacokinetic parameters such as clearance, volume of distribution, half-life, area under the curve, and bioavailability. [1]
Maximum Tolerated Dose Study: A maximum tolerated dose study was conducted in C57/BL6 mice. ML-290 was administered orally once daily for 5 consecutive days at doses of 90, 300, and 3000 mg/kg, followed by a 5-day observation period. No mortality was observed at any dose level. Necropsy after the in vivo studies did not reveal any obvious abnormalities. [1] |
| 药代性质 (ADME/PK) |
In mice, ML-290 demonstrated favorable pharmacokinetic properties. After IV administration (3 mg/kg), plasma clearance was 67.2 mL/min/kg, terminal half-life was 6.6 hours, and volume of distribution at steady state was 24.5 L/kg. [1]
Oral administration (30 mg/kg) resulted in a maximum plasma concentration (Cmax) of 0.30 µg/mL, an AUCinf of 1.00 µg·h/mL, a half-life of 5.5 hours, and an estimated oral bioavailability of 14%. [1] Heart tissue exposure was significantly higher than plasma exposure, with an AUCinf of 5.69 µg·h/mL after IV dosing, indicating good distribution to a target organ for fibrosis. [1] The compound showed excellent stability in both rat and mouse liver microsomes (e.g., mouse microsomal t₁/₂ > 100 minutes for several analogs including ML-290). [1] Kinetic solubility in PBS for ML-290 was 7.0 µM. [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In a 5-day maximum tolerated dose study in mice, oral administration of ML-290 at doses up to 3000 mg/kg did not cause mortality. [1]
No obvious abnormalities were noted upon necropsy in any of the in vivo mammalian studies conducted. [1] The compound showed low cytotoxicity in an ATP-based cell viability assay (EC₅₀ = 18.8 µM). [1] |
| 参考文献 | |
| 其他信息 |
ML-290 represents the first-in-class small-molecule agonist for the relaxin hormone receptor RXFP1, discovered through optimization of a hit from a quantitative high-throughput screen of over 350,000 compounds. [1]
Its activation of RXFP1 leads to an anti-fibrotic gene expression signature, supporting its potential therapeutic utility in treating fibrotic diseases of organs such as the heart, liver, and lungs. [1] A predicted binding model suggests ML-290 binds within the transmembrane domain of RXFP1, forming a critical hydrogen bond between its sulfonyl oxygen and threonine 660 (T660) on extracellular loop 3, which is essential for receptor activation. [1] |
| 分子式 |
C24H21F3N2O5S
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| 分子量 |
506.5
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| 精确质量 |
506.112
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| CAS号 |
1482500-76-4
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| 相关CAS号 |
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| PubChem CID |
56593349
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| 外观&性状 |
White to off-white solid powder
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| 密度 |
1.4±0.1 g/cm3
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| 沸点 |
523.5±50.0 °C at 760 mmHg
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| 闪点 |
270.4±30.1 °C
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| 蒸汽压 |
0.0±1.4 mmHg at 25°C
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| 折射率 |
1.590
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| LogP |
5
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| tPSA |
110
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
8
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| 可旋转键数目(RBC) |
7
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| 重原子数目 |
35
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| 分子复杂度/Complexity |
843
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| 定义原子立体中心数目 |
0
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| InChi Key |
RSYHJSDOGMSLDH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H21F3N2O5S/c1-15(2)34-21-13-6-4-11-19(21)23(31)29-20-12-5-3-10-18(20)22(30)28-16-8-7-9-17(14-16)35(32,33)24(25,26)27/h3-15H,1-2H3,(H,28,30)(H,29,31)
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| 化学名 |
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| 别名 |
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (4.11 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9743 mL | 9.8717 mL | 19.7433 mL | |
| 5 mM | 0.3949 mL | 1.9743 mL | 3.9487 mL | |
| 10 mM | 0.1974 mL | 0.9872 mL | 1.9743 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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