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Purity: ≥98%
CE-224535 is a novel and selective P2X7 receptor antagonist that can be potentially used for the treatment of rheumatoid arthritis and osteoarthritis. Clinical trials showed that CE-224,535 was not efficacious as compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.
CE-224535 (PF-04905428) is a highly potent and selective small-molecule antagonist of the purinergic P2X7 receptor . It functions as an allosteric modulator, binding to the receptor and inhibiting the release of pro-inflammatory cytokines, such as IL-1β and IL-18, from immune cells . In preclinical studies, CE-224535 showed excellent in vitro potency, with IC50 values as low as 4 nM for blocking P2X7 activity, and demonstrated favorable pharmacokinetic properties in animal models . Based on its mechanism of action, it was advanced into clinical trials for the treatment of rheumatoid arthritis (RA). However, a Phase 2/3 study (NCT00628095) concluded that while CE-224535 was safe and tolerable, it did not demonstrate significant efficacy in treating RA patients compared to placebo, leading to the discontinuation of its development for this indication .| Targets |
P2X7 receptor (selective antagonist; inhibits IL-1β and IL-18 release; IC90 for IL-1β release inhibition in ex vivo whole-blood assay estimated at 10 ng/mL) [1]
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| ln Vitro |
CE-224535 is a selective antagonist of the human P2X7 receptor and was created as a disease-modifying antirheumatic medication (DMARD). Rheumatoid arthritis (RA) may now be treated with CE-224535, a novel therapy that can inhibit leukocytes' production of IL-1 and IL-18 [1].
CE-224,535 reduces leukocyte secretion of IL-1β and IL-18, providing a novel therapeutic approach for RA. [1] CE-224,535 potently inhibited the release of IL-1β from ATP-stimulated human monocytes with an IC50 of 1.4 nM. [2] CE-224,535 inhibited ATP-induced uptake of YOPRO-1 in P2X7 receptor-overexpressing HEK293 cells with an IC50 of 4 nM. [2] In the presence of human whole blood, CE-224,535 maintained potent activity with an IC50 of 0.8 nM and an IC90 of 4.7 nM for inhibiting IL-1β release. [2] CE-224,535 (10 µM) showed no significant interaction with a panel of 107 receptors, channels, and transporters. [2] CE-224,535 had no inhibitory effect on major human CYP isozymes (CYP1A2, 2C19, 2C9, 2D6, 3A4) with IC50 values >30 µM. [2] CE-224,535 exhibited weak potency against the mouse P2X7 receptor, with minimal inhibition of ATP-induced IL-1β processing in LPS-activated murine peritoneal macrophages at 10 µM. [2] |
| ln Vivo |
CE-224535 had a half-life of 2.4 hours in rats due to a lower CLp of 11 mL/min/kg and a greater Vdss of 7.6 L/kg. CE-224535 was given orally to rats at a dose of 5 mg/kg, and after that, the maximum plasma exposure (Cmax) was roughly 90 times more than its IC90 in human blood (Cmax=0.21 μg/mL or 0.44 μM). Although CE-224535's oral bioavailability in rats is low (F=2.6%), it is thought to be rat-specific because it is sufficient when it comes to oral bioavailability in dogs (59%) and monkeys (22%).
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| Cell Assay |
An ex vivo whole-blood assay was used to estimate the 90% inhibitory concentration (IC90) for inhibition of IL-1β release by CE-224,535. [1]
The P2X7 receptor antagonist activity of CE-224,535 analogs was evaluated by assessing their ability to inhibit IL-1β release from LPS-activated human monocytes maintained in low serum, stimulated with ATP (final concentration 6 mM). [2] Promising compounds were further evaluated in an analogous assay using human whole blood samples sequentially treated with LPS and ATP. [2] Selected compounds were also tested for their ability to inhibit ATP-induced uptake of YOPRO-1 dye in P2X7 receptor-overexpressing HEK293 cells to provide direct evidence of P2X7 receptor blockade. [2] |
| Animal Protocol |
Pharmacokinetic studies were conducted in rats, dogs, and monkeys. Specific dosing formulations or routes are not detailed, but oral administration was used. [2]
A 4-day toxicology study in rats involved daily oral dosing of CE-224,535 at 500 mg/kg. [2] |
| ADME/Pharmacokinetics |
The median trough concentration of CE-224,535 in plasma was approximately 250 ng/mL, about 25 times the estimated IC90 for inhibiting IL-1β release. The median trough concentration in patients with baseline CRP ≥ 8 mg/L was about twice that in patients with CRP < 8 mg/L, which may be due to the downregulation of CYP3A4 during inflammation. [1]
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| Toxicity/Toxicokinetics |
In patients receiving CE-224,535, 62.3% reported adverse events during treatment, compared to 55.3% in the placebo group. The most common adverse events were nausea (11.3%) and diarrhea (7.5%). Serious adverse events occurred in 3.8% of patients in the CE-224,535 group and 2.1% in the placebo group, and all serious adverse events were considered to be unrelated to treatment. The proportion of patients who discontinued treatment due to adverse events was 9.4% and 6.4%, respectively. [1]
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| References |
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| Additional Infomation |
CE-224535 has been used in clinical trials for the treatment of osteoarthritis. CE-224535 was initially developed as a DMARD for the treatment of rheumatoid arthritis, with a mechanism of action involving inhibition of upstream signaling pathways of IL-1β and IL-18 through P2X7 receptor antagonism. Despite adequate drug exposure, a Phase IIA study showed no significant difference in efficacy compared to placebo. Its safety and tolerability were good. [1]
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| Molecular Formula |
C22H29N4O6CL
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|---|---|
| Molecular Weight |
480.94186
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| Exact Mass |
480.177
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| Elemental Analysis |
C, 54.94; H, 6.08; Cl, 7.37; N, 11.65; O, 19.96
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| CAS # |
724424-43-5
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| PubChem CID |
11547499
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| Appearance |
White to yellow solid powder
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| Density |
1.47g/cm3
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| Index of Refraction |
1.649
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| LogP |
1.532
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
33
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| Complexity |
742
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| Defined Atom Stereocenter Count |
1
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| SMILES |
COC[C@@H](CN1C(=O)C=NN(C1=O)C2=CC(=C(C=C2)Cl)C(=O)NCC3(CCCCCC3)O)O
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| InChi Key |
IRTORRLRMYAEAR-QGZVFWFLSA-N
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| InChi Code |
InChI=1S/C23H30ClN3O6/c1-33-15-17(28)14-26-21(30)13-25-27(22(26)31)16-6-7-19(24)18(12-16)20(29)8-11-23(32)9-4-2-3-5-10-23/h6-7,12-13,17,28,32H,2-5,8-11,14-15H2,1H3/t17-/m1/s1
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| Chemical Name |
2-(4-Chloro-3-(3-(1-hydroxycycloheptyl)propanoyl)phenyl)-4-((2R)-2-hydroxy-3-methoxy-propyl)-1,2,4-triazine-3,5-dione
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| Synonyms |
CE-224,535; CE 224,535; PF-04905428; PF 04905428; PF04905428; CE-224535; T8B02RAU3C; CE224,535; CE-224535; CE 224535; CE224535;
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 (~207.93 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 10 mg/mL (20.79 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 100.0 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: ≥ 10 mg/mL (20.79 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 100.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 10 mg/mL (20.79 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 | 2.0793 mL | 10.3963 mL | 20.7926 mL | |
| 5 mM | 0.4159 mL | 2.0793 mL | 4.1585 mL | |
| 10 mM | 0.2079 mL | 1.0396 mL | 2.0793 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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