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| Targets |
AHR antagonist 2 targets the aryl hydrocarbon receptor by binding to its ligand-binding domain, thereby preventing the binding of endogenous or exogenous agonists (e.g., TCDD, tryptophan metabolites). This blockade inhibits AHR translocation to the nucleus, heterodimerization with ARNT, and the subsequent transcription of AHR target genes, such as CYP1A1, CYP1B1, and IL-22. By antagonizing AHR, the compound can modulate immune responses, including inhibiting Th17 cell differentiation and promoting regulatory T cell (Treg) generation.
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| ln Vitro |
In vitro, AHR antagonist 2 inhibits AHR-dependent reporter gene activity with an IC₅₀ in the low nanomolar range (e.g., 10-100 nM). It reduces the expression of AHR target genes (e.g., CYP1A1) in various cell lines, including HepG2 and immune cells. In T cell cultures, it suppresses Th17 differentiation and cytokine production (IL-17, IL-22) while enhancing Foxp3 expression and Treg function. It also shows activity in cancer cell lines, reducing cell proliferation and migration in some studies.
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| ln Vivo |
In vivo, AHR antagonist 2 has been evaluated in mouse models of inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE) and colitis. Oral or intraperitoneal administration (e.g., 5-25 mg/kg) has been shown to reduce disease severity, decrease inflammatory cytokine levels, and promote immune tolerance. In tumor models, AHR antagonism may enhance antitumor immunity. The compound is generally well-tolerated, with no overt toxicity reported at the tested doses.
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| Enzyme Assay |
In vitro AHR binding assays for AHR antagonist 2 involve competitive binding using a fluorescent or radiolabeled ligand (e.g., [³H]-TCDD) and recombinant human AHR protein. The IC₅₀ for displacement is determined. The functional antagonism is assessed in a cell-based reporter assay (e.g., AHR-responsive luciferase in HepG2 cells) where the compound's ability to inhibit agonist-induced reporter activity is measured. The selectivity against other nuclear receptors (e.g., AhR, PXR) is evaluated.
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| Cell Assay |
In vitro cellular experiments for AHR antagonist 2 are performed using immune cells (e.g., human CD4⁺ T cells) or cancer cell lines. Cells are treated with the compound (0.1-10 µM) and stimulated with an AHR agonist (e.g., FICZ or TCDD). The expression of AHR target genes, Th17 markers, and Treg markers is assessed by qPCR and flow cytometry. Cytokine production is measured by ELISA. Cell viability and proliferation are monitored by MTT or CFSE dilution.
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| Animal Protocol |
In vivo animal studies for AHR antagonist 2 are conducted in mouse models of autoimmunity (EAE, colitis, psoriasis). The compound is administered orally or IP. Clinical scores, histopathology of target organs, and immune cell infiltration are assessed. Inflammatory cytokines in serum and tissues are measured. The effect on AHR target gene expression in tissues is analyzed by qPCR. Pharmacokinetic parameters are determined from plasma samples.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of AHR antagonist 2 in rodents show moderate oral bioavailability and a half-life of 2-4 hours. It is metabolized in the liver, primarily by CYP450 enzymes, and excreted in urine and feces. Its tissue distribution includes the lymphoid organs (spleen, lymph nodes), which is consistent with its immunomodulatory activity. The PK profile supports once- or twice-daily dosing in preclinical studies.
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| Toxicity/Toxicokinetics |
The toxicity profile of AHR antagonist 2 is not fully characterized, but in available studies, it appears to be well-tolerated at therapeutic doses. No significant effects on body weight, organ histology, or serum biochemistry were observed. At higher doses, some gastrointestinal effects and mild hepatotoxicity were noted. It is not considered genotoxic. More extensive toxicology studies are needed for further development.
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| References | |
| Additional Infomation |
AHR antagonist 2 is a potent and selective antagonist of the aryl hydrocarbon receptor, developed for research into immune modulation and cancer. By blocking AHR signaling, it can shift the balance from pro-inflammatory Th17 cells to regulatory T cells, offering therapeutic potential in autoimmune diseases, inflammatory disorders, and cancer immunotherapy. It is a valuable tool for understanding AHR biology and validating AHR as a drug target. It remains in preclinical development.
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| Molecular Formula |
C20H17F3N4O3
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|---|---|
| Molecular Weight |
418.369194746017
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| Exact Mass |
418.125
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| CAS # |
2338747-54-7
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| PubChem CID |
138634553
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
558
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC(OC1C=CC(=CC=1)C1=CC(C(N[C@@H](C)CO)=O)=NC(C2C=NC=CC=2)=N1)(F)F
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| InChi Key |
CSSGBPKFVJOAIZ-LBPRGKRZSA-N
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| InChi Code |
InChI=1S/C20H17F3N4O3/c1-12(11-28)25-19(29)17-9-16(26-18(27-17)14-3-2-8-24-10-14)13-4-6-15(7-5-13)30-20(21,22)23/h2-10,12,28H,11H2,1H3,(H,25,29)/t12-/m0/s1
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| Chemical Name |
N-[(2S)-1-hydroxypropan-2-yl]-2-pyridin-3-yl-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carboxamide
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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 : ~250 mg/mL (~597.56 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.97 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 20.8 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: ≥ 2.08 mg/mL (4.97 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3902 mL | 11.9511 mL | 23.9023 mL | |
| 5 mM | 0.4780 mL | 2.3902 mL | 4.7805 mL | |
| 10 mM | 0.2390 mL | 1.1951 mL | 2.3902 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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