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| Targets |
The primary target of (S)-IDOR-1117-2520 is the CCR6 (C-C chemokine receptor type 6) chemokine receptor, with the compound being the S-isomer of the parent CCR6 antagonist IDOR-1117-2520. CCR6 is a G protein-coupled receptor (GPCR) expressed primarily on T cells, B cells, and dendritic cells. Its sole known ligand is CCL20 (macrophage inflammatory protein-3alpha, MIP-3alpha). The CCR6/CCL20 axis is involved in the pathogenesis of autoimmune diseases including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. IDOR-1117-2520 antagonizes CCL20-mediated calcium influx (IC50 = 63 nM) and beta-arrestin recruitment (IC50 = 30 nM). (S)-IDOR-1117-2520 is a substrate of P-gp/MDR1.
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| ln Vitro |
In cell-free assays, the parent compound IDOR-1117-2520 demonstrates potent antagonism of CCR6. While (S)-IDOR-1117-2520 itself has not been characterized in isolated non-cellular assays, the parent compound‘s activity is well established. Using membrane preparations from cells expressing recombinant human CCR6, competition binding assays with radiolabeled CCL20 would determine binding affinity. The IC50 values against CCL20-mediated calcium flux is 63 nM, and against beta-arrestin recruitment is 30 nM. These data indicate high potency at the receptor level. Selectivity over other chemokine receptors has not been reported in available literature.
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| ln Vivo |
In vitro, the parent compound IDOR-1117-2520 (and presumably its S-isomer) demonstrates potent CCR6 antagonism in cell-based assays. In cells expressing recombinant human CCR6, IDOR-1117-2520 antagonizes CCL20-mediated calcium influx with an IC50 of 63 nM, indicating effective inhibition of G protein-coupled signaling. Additionally, it inhibits beta-arrestin recruitment to human CCR6 with an IC50 of 30 nM, showing effectiveness at blocking both G protein-dependent and beta-arrestin-dependent pathways. These activities suggest the compound acts as a functional antagonist of CCR6-mediated signaling, potentially blocking chemotaxis and inflammatory responses.
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| Enzyme Assay |
In vivo, the parent compound IDOR-1117-2520 is described as orally active and has been used in research of autoimmune diseases and skin inflammation. While detailed in vivo animal protocols for (S)-IDOR-1117-2520 are limited in the available literature, the compound‘s S-isomer likely shares similar properties. Typical in vivo models for CCR6 antagonists include: 1) skin inflammation models (e.g., imiquimod-induced psoriasis-like dermatitis in mice, where CCR6 is involved in gammadelta T cell recruitment) and 2) autoimmune disease models (e.g., collagen-induced arthritis in mice). Oral administration of IDOR-1117-2520 at doses of 1-30 mg/kg would be expected to reduce inflammatory cell infiltration and disease severity scores. (S)-IDOR-1117-2520 is a P-gp/MDR1 substrate, which may affect its pharmacokinetics and CNS exposure.
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| Cell Assay |
For (S)-IDOR-1117-2520, the primary non-cell-based binding assay involves measuring its interaction with CCR6. For the parent compound, assays typically use membranes prepared from HEK293 or CHO cells stably expressing recombinant human CCR6. Radioligand binding assays using [125I]-labeled CCL20 would determine competitive binding affinity (Ki). For functional antagonism, membrane preparations may be used in GTPgammaS binding assays to measure receptor activation. However, specific protocols for non-cellular binding of (S)-IDOR-1117-2520 are not reported. The compound is a substrate of P-gp/MDR1, which can be assessed using ATPase assays or vesicular transport assays with P-gp-containing membranes.
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| Animal Protocol |
For (S)-IDOR-1117-2520 and its parent compound, the primary cell-based assay involves measuring CCR6 antagonism. Cells (e.g., HEK293 or CHO cells) expressing recombinant human CCR6 are loaded with a calcium-sensitive fluorescent dye (such as Fluo-4, Fura-2, or Cal-520) for 30-60 minutes at 37degC. Cells are then pre-incubated with varying concentrations of test compound (0.1 nM - 10 microM) for 15-30 minutes, then stimulated with CCL20 (typically at EC80 concentration). The calcium influx is measured by fluorescence intensity increase using a plate reader (e.g., FLIPR, FlexStation). For beta-arrestin recruitment assays, HEK293 cells co-expressing CCR6 and beta-arrestin-beta-galactosidase or beta-arrestin-luciferase fusion proteins are used, and compound inhibition is measured after stimulation with CCL20. IC50 values are calculated from dose-response curves.
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| ADME/Pharmacokinetics |
For (S)-IDOR-1117-2520 and its parent compound, in vivo studies would typically use rodent models of CCR6-mediated pathology. Common models include: 1) Imiquimod-induced psoriasis-like dermatitis in mice. IDOR-1117-2520 or (S)-IDOR-1117-2520 would be administered orally (by gavage) at doses of 1-30 mg/kg once or twice daily for 7-14 days. Endpoints include: skin thickness, erythema and scaling scores (PASI-like scoring), histopathological analysis of skin sections (epidermal thickness, inflammatory infiltration), and flow cytometry analysis of immune cell populations (gammadelta T cells, Th17 cells). 2) Collagen-induced arthritis (CIA) in mice, where the compound would be administered for 2-4 weeks. Endpoints: clinical arthritis scores, paw swelling, and joint histopathology. (S)-IDOR-1117-2520 is a P-gp/MDR1 substrate, which may limit CNS penetration but is not a primary concern for peripheral inflammatory conditions.
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| Toxicity/Toxicokinetics |
The parent compound IDOR-1117-2520 is described as orally active. However, (S)-IDOR-1117-2520 is identified as a substrate of P-glycoprotein (P-gp/MDR1). This property significantly influences its pharmacokinetic profile, particularly limiting brain penetration and contributing to drug efflux from cells. As a P-gp substrate, the compound may have reduced oral bioavailability and enhanced biliary/renal elimination, potentially requiring higher doses to achieve desired systemic exposure. Detailed PK parameters such as half-life, volume of distribution, Cmax, Tmax, clearance, and absolute oral bioavailability (%) have not been reported in the available literature for this specific S-isomer or its parent compound.
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| References |
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| Additional Infomation |
Specific toxicity data for (S)-IDOR-1117-2520 are not reported in the available literature. The compound is intended for research use only and not for human therapeutic applications. As a chemokine receptor antagonist, potential on-target toxicities could include immune system modulation due to inhibition of CCR6-mediated leukocyte trafficking, which may affect host defense against infections. Off-target effects on other GPCRs cannot be excluded. The compound is a P-gp/MDR1 substrate, which may limit its cellular accumulation and potentially reduce toxicity but also affect efficacy. No acute or chronic toxicity studies have been described. Standard safety precautions for handling should be observed, including use of appropriate personal protective equipment and working in a fume hood.
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| Molecular Formula |
C25H32N4O3
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| Molecular Weight |
436.55
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| Related CAS # |
IDOR-1117-2520; 2737274-49-4
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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 |
| 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 (~229.07 mM; with sonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.73 mM)(saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 of PEG300 and mix thoroughly. Then add 50 μL of Tween-80 to the above system and mix thoroughly. Finally, add 450 μL of physiological saline to bring the volume to 1 mL. Preparation of physiological saline: Dissolve 0.9 g of sodium chloride in ddH₂O and bring the volume to 100 mL to obtain a clear and transparent physiological saline solution. 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 (5.73 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 was added to 900 μL of 20% SBE-β-CD physiological saline solution and mixed thoroughly. 2 g of SBE-β-CD (sulfobutyl ether β-cyclodextrin) powder was diluted to 10 mL of physiological saline and dissolved completely until clear and transparent. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2907 mL | 11.4534 mL | 22.9069 mL | |
| 5 mM | 0.4581 mL | 2.2907 mL | 4.5814 mL | |
| 10 mM | 0.2291 mL | 1.1453 mL | 2.2907 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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