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| Targets |
Formyl Peptide Receptor 2 (FPR2)：BMS-986235 is a selective agonist with EC50 values of 0.41 nM for human FPR2 (hFPR2) and 3.4 nM for mouse FPR2 (mFPR2). It shows >6,800-fold selectivity over human FPR1 (IC50 > 2,800 nM). [1]
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| ln Vitro |
In order to promote the resolution of inflammation, BMS-986235 (LAR-1219) inhibits neutrophil chemotaxis and increases macrophage phagocytosis [1].
- Neutrophil chemotaxis inhibition：BMS-986235 dose-dependently inhibits neutrophil migration induced by the FPR2 agonist WKYMVm, with an IC50 of 0.12 μM in Transwell assays. [1] - Macrophage phagocytosis stimulation：The compound enhances phagocytosis of fluorescently labeled Escherichia coli by macrophages, with a maximal response at 10 nM (2.3-fold increase compared to vehicle control). [1] - G protein activation and β-arrestin recruitment：In HEK293 cells transfected with hFPR2, BMS-986235 triggers Gαi protein activation (measured via cAMP inhibition) and β-arrestin2 recruitment (assessed by bioluminescence resonance energy transfer), with EC50 values of 0.35 nM and 0.82 nM, respectively. [1] |
| ln Vivo |
Following the left anterior descending artery (LAD) in mice, BMS-986235 (LAR-1219) (0.3 mg/kg; oral; once daily for 24 days) decreases left ventricular and overall cardiac remodeling[1]. Cmax, T1/2, AUC0-inf, and bioavailability (BA) values of 160 nmol/L, 0.68 h, and 120 nmol/L were observed with BMS-986235 (1 mg/kg; po) therapy.h, and 24%, in that order[1].
Cardiac remodeling attenuation in mice：Oral administration of BMS-986235 (0.3 mg/kg daily for 24 days) to C57BL/6 mice post-myocardial infarction (MI) reduces left ventricular (LV) chamber dilation by 39% and increases LV ejection fraction by 18% compared to vehicle. Infarct size is decreased by 27% as measured by triphenyltetrazolium chloride (TTC) staining. [1] - Pharmacokinetics in mice：After oral dosing (1 mg/kg), BMS-986235 achieves a Cmax of 160 nM within 0.68 hours, with a plasma half-life of 0.68 hours and oral bioavailability of 24%. Plasma protein binding exceeds 99%. [1] |
| Enzyme Assay |
- FPR2 agonist activity assay：
1. HEK293 cells stably expressing hFPR2 are loaded with a calcium-sensitive dye and stimulated with BMS-986235 (0.01–100 nM).
2. Intracellular calcium mobilization is measured via fluorescence microscopy, with EC50 values calculated from dose-response curves. [1]
- G protein activation assay： 1. Membrane fractions from hFPR2-expressing cells are incubated with BMS-986235 and [³⁵S]GTPγS. 2. G protein activation is quantified by scintillation counting, with EC50 values determined for Gαi subunit activation. [1] |
| Cell Assay |
- Neutrophil chemotaxis assay：
1. Human neutrophils are suspended in migration buffer and added to Transwell inserts.
2. BMS-986235 (0.01–10 μM) or WKYMVm (positive control) is added to the lower chamber.
3. Migrated cells are stained and counted after 90 minutes, with IC50 values calculated for inhibition of WKYMVm-induced migration. [1]
- Macrophage phagocytosis assay： 1. RAW 264.7 macrophages are incubated with fluorescent E. coli particles and BMS-986235 (0.1–100 nM). 2. Phagocytosis is quantified by flow cytometry, measuring mean fluorescence intensity (MFI) of internalized particles. [1] |
| Animal Protocol |
Animal/Disease Models: Male C57BL/6 mice[1]
Doses: 0.3 mg/kg Route of Administration: Po; daily for 24 days Experimental Results: Left ventricle (LV) chamber remodeling is attenuated after myocardial infarction (MI). decreased infarct length by 39% relative to vehicle. Animal/Disease Models: Male mice (BALB/cCrSlc)[1] Doses: 1 mg/kg Route of Administration: Po (pharmacokinetic/PK Analysis) Experimental Results: The Cmax, T1/2, AUC0-inf, and bioavailability (BA) values were 160 nmol/L, 0.68 hrs (hours), 120 nmol/L·h, and 24%, respectively. - MI model in mice： 1. C57BL/6 mice (8–10 weeks old) undergo left anterior descending (LAD) coronary artery ligation to induce MI. 2. Starting 24 hours post-MI, BMS-986235 is administered orally at 0.3 mg/kg daily for 24 days. 3. Cardiac function is assessed by echocardiography at baseline and post-treatment. [1] - Pharmacokinetic study： 1. BALB/c mice receive a single oral dose of BMS-986235 (1 mg/kg) dissolved in a formulation of 10% DMSO, 40% PEG 300, 5% Tween-80, and 45% saline. 2. Plasma samples are collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose. 3. Drug concentrations are measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). [1] |
| ADME/Pharmacokinetics |
Absorption: Rapidly absorbed orally in mice, with a time to peak concentration (Tmax) of 0.68 hours. [1]
- Distribution: High plasma protein binding (>99%) limits the concentration of free drug. [1] - Metabolism: Primarily metabolized in the liver via oxidation and glucuronidation. <5% of the dose is excreted unchanged in urine and feces. [1] - Half-life: 0.68 hours in mice, supporting once-daily administration. [1] |
| Toxicity/Toxicokinetics |
- Acute toxicity: No deaths or adverse reactions were observed in mice after a single oral dose of up to 1000 mg/kg. [1]
- Subchronic safety: No significant changes in hematology, clinical chemistry, or organ weight were observed in rats after daily oral administration of BMS-986235 (0.3–30 mg/kg) for 28 days. [1] |
| References | |
| Additional Infomation |
- Mechanism of action: BMS-986235 activates FPR2, promotes the resolution of macrophage phenotypes (e.g., increased expression of arginase-1 and CD206) and neutrophil apoptosis, thereby reducing inflammation after myocardial infarction. [1] - Therapeutic potential: Studies have found that BMS-986235 can prevent the progression of heart failure after myocardial infarction by enhancing wound healing and limiting adverse remodeling. [1] - Formulation: In preclinical studies, BMS-986235 was administered orally in the form of a DMSO/PEG 300/Tween-80/saline suspension. [1]
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| Molecular Formula |
C18H17F2N3O3
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|---|---|
| Molecular Weight |
361.34269118309
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| Exact Mass |
361.123
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| Elemental Analysis |
C, 59.83; H, 4.74; F, 10.52; N, 11.63; O, 13.28
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| CAS # |
2253947-47-4
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| PubChem CID |
122583088
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| Appearance |
White to off-white solid powder
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| LogP |
2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
504
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| Defined Atom Stereocenter Count |
2
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| SMILES |
N([C@H]1[C@H](C2=C(F)C=C(OC)C=C2F)CNC1=O)C(NC1=CC=CC=C1)=O
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| InChi Key |
FJZNNKJZHQFMCK-LRDDRELGSA-N
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| InChi Code |
InChI=1S/C18H17F2N3O3/c1-26-11-7-13(19)15(14(20)8-11)12-9-21-17(24)16(12)23-18(25)22-10-5-3-2-4-6-10/h2-8,12,16H,9H2,1H3,(H,21,24)(H2,22,23,25)/t12-,16-/m0/s1
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| Chemical Name |
1-[(3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-phenylurea
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| Synonyms |
BMS-986235; 2253947-47-4; BMS 986235; LAR-1219; F8S5G34WY1; 1-((3S,4R)-4-(2,6-Difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-3-phenylurea; LAR1219; BMS986235; compound 13c [PMID: 32407089];
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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 |
| 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) |
DMSO: 100 mg/mL (276.75 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.92 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 25.0 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: ≥ 2.5 mg/mL (6.92 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 1.2 mg/mL (3.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7675 mL | 13.8374 mL | 27.6748 mL | |
| 5 mM | 0.5535 mL | 2.7675 mL | 5.5350 mL | |
| 10 mM | 0.2767 mL | 1.3837 mL | 2.7675 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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