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Purity: ≥98%
ML-290, a 2-acetamido-N-phenylbenzamide analog, is a novel potent, selective and orally bioactive agonist of the relaxin/insulin-like family peptide receptor (RXFP1) and an activator of anti-fibrotic genes with an EC50 of 94 nM. It was identified from a dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line. ML-290 has excellent in vivo PK properties with high levels of systemic exposure. ML-290 represents the first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes.
| Targets |
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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| ln Vitro |
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].
ML-290 (compound 65) is a potent and selective small-molecule agonist of the human RXFP1 receptor. In a cAMP functional assay using HEK293 cells transfected with human RXFP1, ML-290 exhibited an EC₅₀ of 0.094 µM with 98% maximal efficacy relative to forskolin. It showed selectivity over the related RXFP2 receptor and the AVPR1B receptor. [1] In primary human hepatic stellate cells (HSCs) cultured on plastic to induce activation, treatment with 5 µM ML-290 for 24 and 72 hours induced a gene expression profile characteristic of relaxin's anti-fibrotic effects. This included significant downregulation of pro-fibrotic genes (ACTA2, TGFB1, CTGF) and upregulation of matrix metalloproteinase 1 (MMP1) and peroxisome proliferator-activated receptor gamma (PPARG). [1] |
| ln Vivo |
The pharmacokinetic profile of ML-290 was evaluated in male C57/BL6 mice. After intravenous (IV) administration (3 mg/kg), it showed a plasma half-life of 6.6 hours and a high volume of distribution (24.5 L/kg), indicating good tissue penetration. Heart tissue exposure was approximately 6 times higher than plasma exposure after IV dosing. Oral administration (30 mg/kg) resulted in a plasma half-life of 5.5 hours and a bioavailability of 14%. [1]
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| Cell Assay |
cAMP Assay: Cyclic AMP levels were measured to assess RXFP1 activation. HEK293 cells (or THP1 cells) stably or transiently transfected with human RXFP1, RXFP2, or AVPR1B receptors were stimulated with relaxin, test compounds, or forskolin for 30 minutes at 37°C under 5% CO₂. Cellular cAMP was quantified using a homogeneous time-resolved fluorescence (HTRF) detection kit. The assay signal was read on a compatible plate reader. Concentration-response curves were generated, and EC₅₀ values were determined by nonlinear regression analysis. [1]
Gene Expression Modulation in HSCs: Primary human hepatic stellate cells were seeded in poly-L-lysine-coated dishes and grown in specific growth media. Cells were treated in triplicate with either 5 µM ML-290 dissolved in DMSO or DMSO vehicle alone (control) for 24 or 72 hours. Total RNA was extracted, and cDNA was synthesized. Quantitative PCR was performed using gene-specific primers and a master mix. Gene expression levels were normalized to GAPDH, and relative fold changes were calculated using the comparative Ct method. Statistical significance was determined using Student's t-test. [1] |
| Animal Protocol |
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] |
| ADME/Pharmacokinetics |
In mice, ML-290 exhibited good pharmacokinetic properties. After intravenous injection (3 mg/kg), plasma clearance was 67.2 mL/min/kg, terminal half-life was 6.6 h, and steady-state volume of distribution was 24.5 L/kg. [1] After oral administration (30 mg/kg), peak plasma concentration (Cmax) was 0.30 µg/mL, AUCinf was 1.00 µg·h/mL, half-life was 5.5 h, and estimated oral bioavailability was 14%. [1] Cardiac tissue exposure was significantly higher than plasma exposure, with AUCinf of 5.69 µg·h/mL after intravenous injection, indicating that the drug was well distributed to fibrotic target organs. [1] The compound exhibited excellent stability in rat and mouse liver microsomes (e.g., several analogues, including ML-290, had half-lives greater than 100 minutes in mouse microsomes). [1]
ML-290 has a kinetic solubility of 7.0 µM in PBS. [1] |
| Toxicity/Toxicokinetics |
In a 5-day maximum tolerated dose study in mice, oral doses of up to 3000 mg/kg of ML-290 did not result in death. [1]
No significant abnormalities were found in any of the in vivo mammalian studies conducted. [1] The compound showed low cytotoxicity in ATP-based cell viability assays (EC₅₀ = 18.8 µM). [1] |
| References | |
| Additional Infomation |
ML-290 is the first small molecule agonist targeting the relaxin receptor RXFP1, discovered through quantitative high-throughput screening of more than 350,000 compounds. [1] ML-290 activation of RXFP1 induces the expression of antifibrotic genes, supporting its potential therapeutic value in treating fibrotic diseases of organs such as the heart, liver, and lungs. [1] Predicted binding models suggest that ML-290 binds to the transmembrane domain of RXFP1, where its sulfonyl oxygen atom forms a key hydrogen bond with threonine 660 (T660) on the extracellular ring 3, which is crucial for receptor activation. [1]
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| Molecular Formula |
C24H21F3N2O5S
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| Molecular Weight |
506.5
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| Exact Mass |
506.112
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| CAS # |
1482500-76-4
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| Related CAS # |
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| PubChem CID |
56593349
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
523.5±50.0 °C at 760 mmHg
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| Flash Point |
270.4±30.1 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.590
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| LogP |
5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
35
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| Complexity |
843
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| Defined Atom Stereocenter Count |
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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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
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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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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