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| Targets |
C5aR[1]
PMX 205 targets the complement C5a receptor (C5aR or CD88), a G-protein coupled receptor (GPCR) predominantly expressed on immune cells such as neutrophils, macrophages, and T cells. As a selective C5aR1 antagonist, PMX 205 blocks the binding of the pro-inflammatory complement fragment C5a to its cognate receptor. This inhibition prevents the activation of downstream signaling pathways, including phospholipase C, MAP kinases, and NF-kappaB, thereby reducing chemotaxis, degranulation, and the production of pro-inflammatory cytokines. In vitro, PMX 205 does not affect the C5a binding to C5L2, another receptor for C5a, demonstrating functional selectivity. |
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| ln Vitro |
G protein-coupled cell-surface C5aR is activated by complement activation product C5a, which is known to attract and activate microglia and astrocytes in vitro. By comparing each group to the negative control group in the 24-hour plate MTT assay, it is evident that each is significant. The values for the EP54 group, Tamoxifen group, and PMX 205 (PMX205) group range from 0.09893 to 0.2464, 0.02724 to 0.1748, and 0.09880 to 0.2464, respectively. During the 48-hour incubation period, PMX 205 and Tamoxifen are the only two groups exhibiting noteworthy outcomes. Between 0.04987 and 0.3273 and 0.5777 and 0.8551, respectively, are the recorded values. Only PMX 205 (antagonist group), with a value reported between 0.02136 and 0.5322, exhibits a significant result for the 72-hour plate[1].
In vitro characterization of PMX 205 is performed using radioligand binding assays and functional cellular assays. The compound is a potent antagonist, inhibiting C5a-induced calcium flux in human neutrophils or in cells transfected with the C5a receptor. PMX 205 blocks C5a-mediated chemotaxis, respiratory burst, and cytokine release in primary human leukocytes. The effective concentration ranges are typically in the low nanomolar to micromolar range depending on the assay system. In enzyme-based assays, the compound does not directly interact with C5a or complement convertases; its mechanism is receptor-specific antagonism. |
| ln Vivo |
PMX 205, sometimes known as PMX205, is a selective and active oral C5aR antagonist. When compared to rats treated with a vehicle, animals treated with PMX 205 (1 mg/kg/day, oral) show a significant extension of survival time and a reduction in end-stage motor scores. In the lumbar spinal cord, animals treated with PMX 205 also show decreased levels of astroglial growth. PMX 205 (1 mg/kg/day) is administered orally to SOD1G93A rats starting two days (days 28 and 70) prior to the onset of significant clinical signs. The life times of both treatment groups are significantly longer than those of the untreated rats (p=0.022, day 28; p=0.015, day 70), and there are no appreciable changes in the results of the two treatment plans[2]. When Tg2576 mice are 12 to 15 months old—when amyloid deposits in these animals rapidly accumulate—they are given 20 μg/mL of PMX 205 (PMX205) in their drinking water (n=17). Eleven untreated Tg2576 animals serve as the controls. Compared to untreated animals, PMX 205-treated animals have a markedly lower fibrillar plaque load (thioflavine reactivity) after three months. Additionally, PMX 205 dramatically lowers hyperphosphorylated tau (69%) in 3×Tg mice[3].
In vivo, PMX 205 has demonstrated efficacy in multiple animal models of inflammatory disease. In rodent models of sepsis, PMX 205 (1 mg/kg/day, oral) significantly prolongs survival and reduces end-stage motor scores. It is also effective in models of rheumatoid arthritis, asthma, ischemia-reperfusion injury, and neurodegeneration. The compound is orally active, making it suitable for chronic administration regimens. PMX 205 crosses the blood-brain barrier to a limited extent, and it has been evaluated in models of Alzheimer's disease and amyotrophic lateral sclerosis (ALS). The general dosing range in rodents is 0.1-10 mg/kg. |
| Enzyme Assay |
Human C5aR1-expressing cell membranes (20-50 microg protein) are incubated with 0.5-2 nM of a radiolabeled C5a antagonist (e.g., ¹2⁵I-labeled or [3H]C5a) in binding buffer (50 mM HEPES, pH 7.4, 10 mM MgCl2, 100 mM NaCl, 0.5% BSA, 0.1% bacitracin) for 60-90 min at room temperature. Various concentrations of PMX 205 Trifluoroacetate (0.01 nM - 10 microM) are added to the reaction mixture. Nonspecific binding is determined in the presence of 10 microM unlabeled C5a. Bound radioligand is separated by rapid filtration through GF/B or GF/C filters presoaked in 0.3% polyethyleneimine. Filters are washed 3 times with ice-cold binding buffer and radioactivity is quantified by liquid scintillation counting or gamma counting. Ki values are calculated from IC50 using the Cheng-Prusoff equation.
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| Cell Assay |
HEK293 cells stably expressing human C5aR1 (HEK-C5aR) are seeded in black-walled 96-well plates (3-5×10⁴ cells/well) and incubated overnight. Cells are washed with HBSS (Hanks' Balanced Salt Solution) containing 20 mM HEPES, 0.1% BSA, and 2.5 mM probenecid. Cells are loaded with 2-4 microM Fluo-4 AM (a calcium-sensitive fluorescent dye) for 30-45 min at 37degC in the dark. After washing, cells are preincubated with varying concentrations (0.01 nM - 10 microM) of PMX 205 for 10-15 min at room temperature. C5a (1-10 nM, an agonist) is automatically injected into each well, and the fluorescence increase (ex/em = 485/535 nm) is measured immediately for 60-120 seconds using a FlexStation or FLIPR instrument. The peak fluorescence signal is recorded. Percent inhibition is calculated relative to the C5a-only control. The IC50 value is determined by nonlinear regression using a four-parameter logistic equation. For selectivity testing, a similar protocol is performed using VP-labeled C5a or C5a peptides, and the experiment is repeated using a C5aR2 (C5L2) expressing cell line to confirm selectivity.
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| Animal Protocol |
Animal models of sepsis are commonly used. Male BALB/c or C57BL/6 mice (8-10 weeks, 20-25 g, n=10-15 per group) are injected intraperitoneally with LPS (E. coli 0111:B4, 15-20 mg/kg) or cecal ligation and puncture (CLP) to induce polymicrobial sepsis. PMX 205 Trifluoroacetate (dissolved in 0.5% methylcellulose, 10% DMSO + 40% PEG300 + 50% saline, or sterile PBS) is administered orally (p.o.) by gavage at doses of 0.5, 1, or 5 mg/kg once daily for 3-7 days. Treatment is initiated immediately after sepsis induction. Survival is monitored for 7-14 days. At designated time points (e.g., 6, 24, 48 h), blood is collected, and serum levels of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IL-10) are measured by ELISA. Lung, liver, and kidney tissues are collected for assessment of myeloperoxidase (MPO) activity (as a marker of neutrophil infiltration), histopathological analysis (H&E staining), and measurement of cytokine levels by qPCR. For a collagen-induced arthritis (CIA) model, DBA/1J mice are immunized with bovine type II collagen in CFA, and a booster is given on day 21. PMX 205 (1-5 mg/kg/day p.o.) is administered from day 21 to day 42. Clinical arthritis scores are evaluated every 2-3 days, and paw thickness is measured using a caliper. Plasma samples are collected for cytokine analysis, and joint tissues are collected for histological scoring (inflammation, pannus formation, cartilage damage, bone erosion) after safranin O staining.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic parameters of PMX 205 have not been fully published. However, as a cyclic peptide, it is expected to have improved stability compared to linear peptides, but oral bioavailability is limited (likely <20-30% in rodents). In mice, oral administration at 1 mg/kg/day produces detectable plasma concentrations sufficient for efficacy. The compound is soluble in DMSO (>100 mg/mL) and is poorly soluble in water (<0.1 mg/mL). For in vivo administration, a formulation of 10% DMSO, 40% PEG300, 5% Tween 80, and 45% saline is recommended to achieve ≥2.5 mg/mL solubility. The elimination half-life in rodents is likely 1-4 hours, requiring once or twice daily dosing for sustained receptor occupancy.
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| Toxicity/Toxicokinetics |
No detailed toxicology data have been published for PMX 205 Trifluoroacetate. In animal efficacy studies, the compound was generally well-tolerated at doses up to 5-10 mg/kg (oral or intraperitoneal) for 14-28 days, with no overt signs of systemic toxicity, such as significant body weight loss, behavioral changes, or mortality. As a complement C5a receptor antagonist, the primary mechanism-based safety concerns include an increased susceptibility to certain bacterial infections, as the C5a axis is important for innate immunity. No genotoxicity or cardiotoxicity data are available. Standard laboratory safety practices should be followed when handling this compound.
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| References |
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| Additional Infomation |
PMX 205 Trifluoroacetate is a research-grade compound and is not approved by the FDA, EMA, or any other regulatory agency for clinical use. It is a potent, selective, and orally active C5aR1 antagonist used as a pharmacological tool to study complement C5a-mediated inflammatory pathways. The compound is distinct from PMX 53, another well-known C5aR antagonist. PMX 205 has higher stability and receptor selectivity compared to PMX 53. This product is for research use only and not for human therapeutic applications. Store as a lyophilized powder at -20degC in a sealed container, protected from moisture.
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| Molecular Formula |
C47H63F3N10O8
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| Molecular Weight |
953.06
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| Related CAS # |
PMX 205;514814-49-4
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| Appearance |
White to off-white solid powder
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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 (~104.93 mM)
H2O :< 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.62 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 (2.62 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 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: ≥ 2.5 mg/mL (2.62 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 | 1.0493 mL | 5.2463 mL | 10.4925 mL | |
| 5 mM | 0.2099 mL | 1.0493 mL | 2.0985 mL | |
| 10 mM | 0.1049 mL | 0.5246 mL | 1.0493 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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