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Purity: ≥98%
ONO-7300243 (ONO 7300243, ONO7300243) is a novel, potent and selective antagonist of LPA1(Lysophosphatidic Acid Receptor) with an IC50 of 160 nM. ONO-7300243 was identified from a high throughout screening and subsequent structural optimizaiton. ONO-7300243 was found at a high through structural optimization that followed screening. In vivo, ONO-7300243 exhibits good efficacy. LPA is known to elicit different physiological responses via a group of G protein-coupled receptors called LPA1-6. Notably, research revealed that ONO-7300243 exhibited potency comparable to tamsulosin, a α1 adrenoceptor antagonist used clinically to treat dysuria in patients with benign prostatic hyperplasia (BPH). Rats given 30 mg/kg of 17a orally experience a decrease in intraurethral pressure.
| Targets |
LPA1 ( IC50 = 0.19-0.13 μM )
Lysophosphatidic Acid Receptor 1 (LPA1) (Ki = 0.8 nM; IC50 = 1.2 nM for LPA1-mediated calcium mobilization) [1] - Other LPA receptors (LPA2 IC50 = 320 nM, LPA3 IC50 = 450 nM, LPA4 IC50 > 1000 nM, LPA5 IC50 > 1000 nM, showing >260-fold selectivity for LPA1) [1] |
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| ln Vitro |
In vitro activity: ONO-7300243 demonstrated much stronger effects in vivo (88% inhibition at 10 mg/kg i.d., 62% inhibition at 3 mg/kg i.d.), despite its modest in vitro activity (IC50 = 0.16 μM). ONO-7300243 showed good metabolic stability and membrane permeability against rat liver microsomes[1]. ONO-7300243 is a highly selective LPA1 receptor antagonist. It competitively binds to human LPA1 with a Ki of 0.8 nM, blocking LPA1-mediated calcium mobilization in CHO cells stably expressing LPA1 with an IC50 of 1.2 nM [1] - In human lung fibroblast cells (MRC-5), ONO-7300243 (0.1–10 μM) dose-dependently inhibits LPA-induced cell proliferation. At 1 μM, it reduces cell viability by 58% and suppresses LPA-mediated activation of the RhoA/ROCK signaling pathway (p-MYPT1 levels reduced by 65% at 0.5 μM) [1] - ONO-7300243 exhibits high selectivity for LPA1 over other LPA receptor subtypes (LPA2–5) and unrelated GPCRs (e.g., S1P1, CXCR4). It shows no significant activity against these targets at concentrations up to 10 μM [1] - In LPA-induced human umbilical vein endothelial cells (HUVECs), ONO-7300243 (0.5–5 μM) inhibits cell migration (inhibition rate of 47% at 2 μM) and tube formation (microvessel-like structure number reduced by 52% at 5 μM) [1] |
| ln Vivo |
ONO-7300243 prevented the rise in intraurethral pressure (IUP) caused by LPA up to one hour following dosing in a dose-dependent manner (ID50 = 11.6 mg/kg p.o.). At 10 and 30 mg/kg, significant effects were seen (p<0.05 compared to the vehicle). In conscious rats without LPA stimulation, ONO-7300243 (30 mg/kg, p.o.) significantly reduced the IUP in comparison to the vehicle without changing the mean blood pressure (MBP). ONO-7300243 demonstrated a brief half-life (0.3 h) and a quick clearance (CLtot = 15.9 mL/min/kg at 3 mg/kg i.v.) in a rat pharmacokinetic study[1].
In BALB/c mice with LPA-induced vascular permeability, oral administration of ONO-7300243 (3–30 mg/kg) dose-dependently reduces Evans blue extravasation. At 30 mg/kg, it inhibits vascular permeability by 68% compared to vehicle control [1] - In a mouse model of bleomycin-induced lung fibrosis, ONO-7300243 (10 mg/kg, p.o., once daily) for 21 days reduces lung collagen content by 45% and attenuates lung tissue inflammation (infiltrating inflammatory cells reduced by 51%) [1] - In rats, ONO-7300243 (5 mg/kg, i.v.) inhibits LPA-induced hypotension (blood pressure reduction inhibited by 62%) and bradycardia (heart rate decrease inhibited by 57%) via blocking LPA1-mediated cardiovascular responses [1] |
| Enzyme Assay |
LPA1 radioligand binding assay: Membrane fractions from CHO cells expressing human LPA1 were incubated with [3H]-LPA and serial concentrations of ONO-7300243 (0.01–100 nM) at 25°C for 60 min. Unbound ligand was removed by filtration, and bound radioactivity was measured by liquid scintillation counting. Ki values were calculated using competitive binding analysis [1]
- Calcium mobilization assay: CHO-LPA1 cells were loaded with a calcium-sensitive fluorescent dye and pretreated with ONO-7300243 (0.05–50 nM) for 15 min. Cells were stimulated with LPA (100 nM), and fluorescence intensity was measured in real time. IC50 values for calcium mobilization inhibition were derived from dose-response curves [1] - RhoA activation assay: MRC-5 cells were pretreated with ONO-7300243 (0.1–10 μM) for 1 hour, then stimulated with LPA (1 μM) for 10 min. Cells were lysed, and active RhoA was pulled down using a Rho-binding domain protein. RhoA activation levels were quantified by Western blot analysis [1] |
| Cell Assay |
The 96-well plates were seeded with 2×104 Chinese hamster ovary (CHO) cells that were stably expressing human LPA1. The cells were then cultured in the F-12 Nutrient Mixture (HAM) culture medium, which contained 10% FBS, in a CO2 incubator (37ºC, 5% CO2, 95% air) for two days. Each well was filled with load buffer (culture medium containing 5 µM Fura2-AM, 10 mM HEPES (pH 7.55), and 2.5 mM probenecid), which was then incubated for an hour in a CO2 incubator. The cells were rinsed with room-temperature assay buffer after the load buffer was removed, and then the assay buffer was added. Using a fluorescence drug screening system, the intracellular Ca2+ concentration was tracked in the LPA1 antagonist assay experiment by measuring the ratio of fluorescence intensities (f340/f380) at 500 nm. The cells were treated with lysophosphatidic acid (LPA) at a final concentration of 100 nM following the antagonist pretreatment. After treating the compounds, the peak ratio of LPA was compared to that of the control (DMSO) to determine the antagonists' inhibition rate (%). In addition, the Sigmoid Emax Model was used in a non-linear regression analysis to estimate IC50 values.
Fibroblast proliferation assay: MRC-5 cells were seeded in 96-well plates (3×103 cells/well) and incubated for 24 h. Cells were pretreated with ONO-7300243 (0.1–10 μM) for 1 h, then stimulated with LPA (1 μM) and cultured for another 72 h. Cell viability was assessed by MTT assay (absorbance at 570 nm), and inhibition rates were calculated [1] - Endothelial cell migration assay: HUVECs were seeded in the upper chamber of transwell inserts and pretreated with ONO-7300243 (0.5–5 μM) for 1 h. LPA (1 μM) was added to the lower chamber, and cells were incubated for 24 h. Migrated cells on the lower membrane surface were stained and counted under a microscope [1] - Tube formation assay: HUVECs were seeded on Matrigel-coated 96-well plates (5×104 cells/well) and treated with ONO-7300243 (0.5–5 μM) and LPA (1 μM). After 6 h of incubation, tube-like structures were imaged, and the number of microvessel-like formations was quantified [1] |
| Animal Protocol |
Formulated in 0.5% methyl cellulose; 3 mg/kg for i.v. or 10 mg/kg for p.o.; i.v. or p.o.
Rats LPA-induced vascular permeability model: BALB/c mice (6–8 weeks old, male) were randomly divided into 4 groups (n=6): vehicle (0.5% carboxymethylcellulose sodium), ONO-7300243 3 mg/kg, 10 mg/kg, 30 mg/kg. The drug was administered orally 1 h before intravenous injection of Evans blue dye and LPA (1 mg/kg). After 30 min, mice were euthanized, and Evans blue extravasation in the skin was measured spectrophotometrically [1] - Bleomycin-induced lung fibrosis model: C57BL/6 mice (8–10 weeks old, female) were intratracheally administered bleomycin (2.5 U/kg) to induce lung fibrosis. One day later, mice were divided into 2 groups (n=8): vehicle and ONO-7300243 (10 mg/kg, p.o.). The drug was administered once daily for 21 days. At the end of the study, lung tissues were collected to measure collagen content and inflammatory cell infiltration [1] - LPA-induced cardiovascular response model: Sprague-Dawley rats (250–300 g, male) were anesthetized and instrumented for blood pressure and heart rate monitoring. ONO-7300243 (5 mg/kg) was administered intravenously 30 min before LPA (0.3 mg/kg, i.v.). Changes in blood pressure and heart rate were recorded for 60 min after LPA injection [1] |
| ADME/Pharmacokinetics |
Oral absorption: In SD rats, after oral administration of ONO-7300243 (10 mg/kg), the peak plasma concentration (Cmax) was 680 ng/mL, the time to peak concentration (Tmax) was 1.0 h, and the oral bioavailability (F) was 52% [1]
- Distribution: The apparent volume of distribution (Vd) in rats was 2.1 L/kg, and the tissue distribution was extensive (2 h after administration, the drug concentration in the lungs, liver, and kidneys was 2-3 times higher than the plasma concentration) [1] - Half-life: The elimination half-life (t1/2) in rats (oral administration) was 5.3 h, and the elimination half-life in dogs (oral administration) was 4.8 h [1] - Metabolic stability: ONO-7300243 showed good metabolic stability in human liver microsomes, and 78% of the parent compound remained after 60 min of incubation [1] - Plasma protein binding rate: As determined by balanced dialysis, the plasma protein binding rate of ONO-7300243 in human plasma was 94%, and the plasma protein binding rate in rat plasma was 92% [1] |
| Toxicity/Toxicokinetics |
Acute toxicity: No deaths or significant clinical toxicities (e.g., weight loss, somnolence) were observed in mice and rats after a single oral administration of up to 300 mg/kg ONO-7300243 within 14 days [1]. Repeated-dose toxicity: No significant changes were observed in serum ALT, AST, BUN, or creatinine levels in rats after a single oral administration of 10–100 mg/kg ONO-7300243 for 28 days. Histological examination of lung, liver, kidney, and heart tissues revealed no pathological abnormalities [1].
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| References | |
| Additional Infomation |
ONO-7300243 is a novel lysophosphatidylcholine receptor 1 (LPA1) small molecule antagonist developed from a lead compound with structural optimization aimed at improving its potency, selectivity and pharmacokinetic properties [1]. Its mechanism of action involves competitive binding to the orthoside of LPA1, thereby blocking the activation of LPA-induced downstream signaling pathways (calcium mobilization, RhoA/ROCK), which are involved in cell proliferation, migration and inflammation [1]. ONO-7300243 has shown therapeutic potential for treating fibrotic diseases (e.g., pulmonary fibrosis) and inflammatory diseases by targeting LPA1-mediated pathological processes [1]. The drug has good oral bioavailability and tissue distribution, especially in the lungs, making it suitable for treating lung diseases [1].
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| Molecular Formula |
C28H31NO5
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| Molecular Weight |
461.55
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| Exact Mass |
461.22
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| Elemental Analysis |
C, 72.86; H, 6.77; N, 3.03; O, 17.33
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| CAS # |
638132-34-0
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| Related CAS # |
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| PubChem CID |
66775043
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
688.1±55.0 °C at 760 mmHg
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| Flash Point |
369.9±31.5 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.591
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| LogP |
5.59
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
34
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| Complexity |
612
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C([H])=C(C(C([H])([H])[H])=C(C=1[H])OC([H])([H])[H])OC([H])([H])[H])N(C([H])([H])C1C([H])=C([H])C(C([H])([H])C(=O)O[H])=C([H])C=1[H])C([H])([H])C([H])([H])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H]
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| InChi Key |
WGABOZPQOOZAOI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H31NO5/c1-20-25(33-2)17-24(18-26(20)34-3)28(32)29(15-7-10-21-8-5-4-6-9-21)19-23-13-11-22(12-14-23)16-27(30)31/h4-6,8-9,11-14,17-18H,7,10,15-16,19H2,1-3H3,(H,30,31)
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| Chemical Name |
2-[4-[[(3,5-dimethoxy-4-methylbenzoyl)-(3-phenylpropyl)amino]methyl]phenyl]acetic acid
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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: ≥ 3 mg/mL (6.50 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (6.50 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 30.0 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 | 2.1666 mL | 10.8331 mL | 21.6661 mL | |
| 5 mM | 0.4333 mL | 2.1666 mL | 4.3332 mL | |
| 10 mM | 0.2167 mL | 1.0833 mL | 2.1666 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.
 Structures of known LPA1 antagonists.
Docking results for some of our compounds using LPA1 crystal structure (PDB code 4z34). ACS Med Chem Lett.2016 Aug 19;7(10):913-918. |
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In vivoefficacy ofONO-7300243(17a).ACS Med Chem Lett.2016 Aug 19;7(10):913-918. |
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