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| Targets |
JR-14a targets the human complement C3a receptor (C3aR), a G protein-coupled receptor that is activated by the complement component C3a. C3aR is involved in inflammatory responses, including chemotaxis, mast cell degranulation, and cytokine production. JR-14a is a selective antagonist of C3aR, with high selectivity for C3aR over the C5a receptor. By blocking C3aR, JR-14a inhibits C3a-mediated signaling and suppresses inflammatory responses. The compound's thiophene-based structure contributes to its potency and selectivity for C3aR.
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| ln Vitro |
JR14a cells, whose IC50 ranges from 0.1 nM to 100 μM, have been shown to block C3a-induced internal Ca2+ release in human monocyte-derived macrophages[1]. An IC50 of 8 nM is observed in human LAD2 mast cells exposed to intravenous injection of JR14a (0.1 nM-100 μM) to inhibit C3a β-hexosaminidase [1].
In vitro, JR-14a potently inhibits C3a-induced responses. The compound inhibits C3a-induced intracellular calcium release in human monocyte-derived macrophages with an IC50 of 10 nM. JR-14a also inhibits β-hexosaminidase secretion from human LAD2 mast cells degranulated by C3a with an IC50 of 8 nM. The compound shows high selectivity for C3aR over C5aR, with no significant inhibition of C5a-mediated responses. JR-14a effectively suppresses C3aR-mediated inflammatory responses in various cell types. |
| ln Vivo |
JR14a (10 mg/kg; po 2 h before) induced 65% more paw swelling than controls 30 minutes after hemostatic injection in an acute state paw model of edema and edema [1]. JR14a (1 mg/kg; iv) exhibited elimination half-life (191 minutes), clearance (4.4 mL/min/kg), and AUC (3795 ng·h/mL) at shelf [1]. JR14a (10 mg/kg; po) exhibited Cmax (88 ng/mL), Tmax (300 min), and AUC (478 ng h/mL) at shelf [1].
In vivo, JR-14a (10 mg/kg, oral administration 2 hours prior) reduces paw swelling by 65% over control at 30 minutes after agonist injection in an acute rat paw model of inflammation and edema. The compound's oral bioavailability and efficacy in this model demonstrate its potential as a therapeutic agent for complement-mediated inflammatory conditions. JR-14a's ability to suppress C3aR-mediated inflammation suggests applications in diseases such as rheumatoid arthritis, asthma, and ischemia-reperfusion injury. |
| Enzyme Assay |
JR-14a's antagonism of C3aR is assessed using functional assays. Cells expressing C3aR (e.g., human monocyte-derived macrophages, LAD2 mast cells) are treated with varying concentrations of JR-14a, then stimulated with C3a; intracellular calcium release is measured using fluorescent calcium indicators; β-hexosaminidase secretion is measured by enzymatic assay; selectivity for C3aR over C5aR is assessed by comparing activity in C3a-stimulated versus C5a-stimulated cells. IC50 values are calculated from dose-response curves. These assays provide quantitative information on the potency and selectivity of JR-14a.
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| Cell Assay |
JR-14a is tested on cultured cells expressing C3aR, including human monocyte-derived macrophages and LAD2 mast cells. Cells are treated with varying concentrations of JR-14a, then stimulated with C3a; intracellular calcium release is measured using fluorescent calcium indicators; β-hexosaminidase secretion is measured by enzymatic assay; cytokine production is measured by ELISA; chemotaxis is assessed using transwell migration assays. These cell-based assays demonstrate the mechanism of action and anti-inflammatory activity of JR-14a.
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| Animal Protocol |
Animal/Disease Models: Male Wister rats (8 weeks, 250-300 g) were injected with BR103[1].
Doses: 10 mg/kg Route of Administration: Oral 2 hrs (hrs (hours)) before agonist challenge Experimental Results: Inhibits C3aR-mediated inflammation. Animal/Disease Models: Male Wister rat (8 weeks, 250-300 g) [1] Doses: 1 mg/kg, intravenous (iv) (iv)injection; oral 10 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)administration and oral administration Dosing Experimental Results: IV: t1/2=191 min, clearance=4.4 mL/min/kg, AUC=3795 ng·h/mL. Po: Cmax=88 ng/mL, Tmax=300 minutes, AUC=478 ng·h/mL. JR-14a is evaluated in animal models of inflammation and edema. In the acute rat paw model of inflammation and edema, JR-14a (10 mg/kg, oral administration 2 hours prior) reduces paw swelling by 65% over control at 30 minutes after agonist injection. Additional models may include asthma, arthritis, and ischemia-reperfusion injury models. These in vivo studies provide evidence for the efficacy and oral bioavailability of JR-14a. |
| ADME/Pharmacokinetics |
Pharmacokinetic studies indicate that JR-14a is orally bioavailable. The compound's absorption, distribution, metabolism, and excretion have been characterized in preclinical studies. JR-14a achieves therapeutic concentrations in plasma and tissues following oral administration. The compound's pharmacokinetic properties support oral dosing in clinical development.
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| Toxicity/Toxicokinetics |
The toxicity profile of JR-14a is not extensively characterized in the available literature. As a C3aR antagonist, JR-14a is expected to have a favorable safety profile, given the role of C3aR in inflammatory responses. However, comprehensive toxicological studies are needed to evaluate the safety profile of JR-14a.
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| References | |
| Additional Infomation |
JR-14a is a potent, orally bioavailable C3a receptor antagonist with IC50 values of 8 nM in human mast cell degranulation and 10 nM in macrophage Ca2+ release. The compound shows high selectivity for C3aR over C5aR and effectively suppresses C3aR-mediated inflammatory responses. JR-14a has shown efficacy in reducing paw swelling in an acute rat model of inflammation and edema. The compound represents a promising therapeutic approach for complement-mediated inflammatory conditions, including rheumatoid arthritis, asthma, and ischemia-reperfusion injury. JR-14a is not approved as a therapeutic agent and is used for research purposes only.
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| Molecular Formula |
C25H26CL2N4O3S
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| Molecular Weight |
533.469942569733
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| Exact Mass |
532.11
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| CAS # |
2411440-41-8
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| Related CAS # |
2417323-15-8 (TFA);2411440-41-8;
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| PubChem CID |
145996525
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| Appearance |
White to light yellow solid powder
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| LogP |
5
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
35
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| Complexity |
716
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1C=CC(=CC=1)C(C1C=CC(=CC=1)Cl)C1=CC(C)=C(C(N[C@H](C(=O)O)CCC/N=C(\N)/N)=O)S1
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| InChi Key |
OHRIKWUZKGNQKQ-IBGZPJMESA-N
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| InChi Code |
InChI=1S/C25H26Cl2N4O3S/c1-14-13-20(21(15-4-8-17(26)9-5-15)16-6-10-18(27)11-7-16)35-22(14)23(32)31-19(24(33)34)3-2-12-30-25(28)29/h4-11,13,19,21H,2-3,12H2,1H3,(H,31,32)(H,33,34)(H4,28,29,30)/t19-/m0/s1
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| Chemical Name |
(2S)-2-[[5-[bis(4-chlorophenyl)methyl]-3-methylthiophene-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid
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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 (~187.45 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.69 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 (4.69 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. 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 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: 2.5 mg/mL (4.69 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8745 mL | 9.3726 mL | 18.7452 mL | |
| 5 mM | 0.3749 mL | 1.8745 mL | 3.7490 mL | |
| 10 mM | 0.1875 mL | 0.9373 mL | 1.8745 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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