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| Targets |
The compound targets CXCR3 (C-X-C motif chemokine receptor 3), a G-protein-coupled receptor (GPCR) expressed primarily on activated T cells (Th1 cells), CD8+ T cells, and natural killer (NK) cells. Its natural ligands are CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC). CXCR3 plays a key role in the recruitment of inflammatory T cells to sites of inflammation, including the lungs, skin, and central nervous system, making it a validated target for autoimmune and inflammatory diseases.
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| ln Vitro |
ACT-660602, with IC50s of 18 μM (hERG), demonstrates selectivity to CXCR3 over hERG[1]. Improved metabolic stability and inhibition of cell migration are two benefits of ACT-660602 (112 nM; 6 h)[1]. With more constant IC50s, ACT-660602 (5, 20, 100, or 500 nM) exhibits a non-competitive binding mechanism to CXCL10 and CXCL11 at varying concentrations[1].
ACT-660602 is an antagonist of CXCR3 with an IC50 of 204 nM in biochemical or cellular binding/activity assays. The compound inhibits T cell migration toward CXCR3 ligands, which is the primary mechanism by which CXCR3 contributes to inflammation. By blocking CXCR3, ACT-660602 prevents the infiltration of Th1-type and CD8+ T cells into inflamed tissues, thereby reducing tissue damage and inflammation in autoimmune disease models. |
| ln Vivo |
Intrinsic metabolic clearance (CLint) of ACT-660602 (1 μM; 6 h) in human, rat, and mouse liver microsomes (HLM, RLM, MLM)[1]. In the mouse model of acute lung injury, ACT-660602 (30 mg/kg; po; once daily) has anti-inflammatory action and shows efficacy[1]. Pharmacokinetic range for ACT-660602[1] Animal Route Dose (range) (mg/kg) Cmax (range) (ng/mL) Tmax (range) (h) AUC (range) (ng·h/mL) F (%) CL (range) (mL/min/kg) Vss (range) (L/kg) T1/2 (range) (h) Dog po 2 1380 1 20000 8 1.3 1.7 14.5 iv 0.5 1300-1450 0.5-2.0 10400-32000 / 0.6-3.0 1.6-1.7 6.3- Rat po 2 1520 0.5 14000 80 1.9 7.1 iv 0.5 1250-1860 0.5-1.0 11600- 15641 / 1.9-1.9 0.9-1.3 5.7-8.8
ACT-660602 has been shown to have significant efficacy in an in vivo model of acute lung injury, blocking T cell migration and reducing inflammation. It is also expected to show efficacy in other autoimmune disease models, such as the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, the imiquimod-induced psoriasis model, and the DSS-induced colitis model. A typical protocol would involve oral administration of the compound to mice (e.g., 10-50 mg/kg once or twice daily) and assessment of clinical disease scores, histological analysis, and T cell infiltration into target tissues. |
| Enzyme Assay |
The CXCR3 antagonism assay is typically performed using a radioligand binding or a functional GTPgammaS binding assay. Membranes prepared from CHO or HEK293 cells stably expressing human CXCR3 are incubated with a radiolabeled CXCR3 ligand (e.g., 125I-CXCL10 or 125I-IP-10) and varying concentrations of ACT-660602 (0.1-1000 nM) in binding buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 5 mM MgCl2, 1 mM EDTA, 0.1% BSA). After incubation at room temperature for 60-90 minutes, the mixture is filtered through GF/B filters, and bound radioactivity is measured by scintillation counter to calculate the IC50/Ki.
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| Cell Assay |
Cell Migration Assay [1]
Cell Types: CD3/CD28-activated primary human T cells Tested Concentrations: 112 nM Incubation Duration: 45 min Experimental Results: Inhibited cell migration. A functional chemotaxis assay is performed using primary human T cells or a CXCR3-expressing cell line (e.g., Ba/F3 cells transfected with CXCR3). Cells are labeled with a fluorescent dye (e.g., Calcein-AM) and placed in the upper chamber of a 96-well Transwell plate. The lower chamber contains one of the CXCR3 ligands (e.g., CXCL10/IP-10 at 10-100 ng/mL). ACT-660602 is added to the cells in the upper chamber at varying concentrations (0.1-1000 nM). After 2-4 hours of incubation at 37degC, migrated cells in the lower chamber are quantified by fluorescence measurement. The IC50 for inhibition of chemotaxis is calculated from the dose-response curve. |
| Animal Protocol |
Animal/Disease Models: LPS-induced lung inflammation model (72 h post LPS challenge)[1]
Doses: 30 mg/kg Route of Administration: po (oral gavage); one time/day Experimental Results: Dramatically decreased recruitment of the CXCR3+ CD8+ T cell in the bronchialveolar lavage compartment. ACT-660602 has shown efficacy in an acute lung injury (ALI) model. A typical protocol uses the LPS-induced acute lung injury mouse model. Female C57BL/6 mice are administered ACT-660602 via oral gavage at doses of 10, 30, or 100 mg/kg one hour before intratracheal administration of LPS (5 mg/kg). After 6-24 hours, bronchoalveolar lavage (BAL) fluid is collected to measure total cell count, neutrophil infiltration (by flow cytometry or differential staining), and protein levels (a marker of lung permeability). Lung tissues are harvested for histopathological analysis (H&E staining), myeloperoxidase (MPO) activity measurement, and cytokine levels (TNF-alpha, IL-6, CXCL1). Total T cell and CD8+ T cell infiltration into the lung tissue is analyzed by flow cytometry. |
| ADME/Pharmacokinetics |
As an orally active compound, ACT-660602 is designed for oral administration. Specific quantitative PK parameters are not detailed; however, its classification as an oral CXCR3 antagonist indicates favorable oral bioavailability. Key PK parameters such as half-life, Cmax, AUC, and volume of distribution would be determined empirically. The compound's ability to reach inflamed tissues and the degree of tissue distribution would also be evaluated.
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| Toxicity/Toxicokinetics |
Specific toxicological data for ACT-660602 are not detailed. As a CXCR3 antagonist that blocks the recruitment of T cells to sites of inflammation, the primary on-target safety concern would be an increased susceptibility to infections, particularly viral and intracellular bacterial infections where Th1-type T cells play a protective role. However, CXCR3 knockout mice are viable and have no major developmental defects, suggesting the target may be safe for inhibition. Standard toxicological endpoints in animal studies would include monitoring body weight, signs of infection, and immune cell populations in peripheral blood.
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| References |
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| Additional Infomation |
ACT-660602 is a research-grade chemical tool and a clinical-stage candidate for autoimmune diseases. CXCR3 and its ligands (CXCL9, CXCL10, CXCL11) are upregulated in many autoimmune and inflammatory conditions, including rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and acute lung injury. By blocking T cell recruitment, ACT-660602 offers a targeted approach to reducing inflammation without globally suppressing the immune system. As of the latest updates, the compound is in pre-clinical or early clinical development and has not yet been approved for medical use.
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| Molecular Formula |
C20H20F6N8OS
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|---|---|
| Molecular Weight |
534.48122215271
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| Exact Mass |
534.138
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| CAS # |
1646267-59-5
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| PubChem CID |
87056189
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| Appearance |
White to off-white solid powder
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| LogP |
3.6
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
36
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| Complexity |
782
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C(=O)(N1CCN(C2SC(C(F)(F)F)=NC=2C2=CN=C(C(F)(F)F)N=C2)C[C@H]1C)CN1C(C)=NC(C)=N1
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| InChi Key |
JENUMEXEVAAAJX-SNVBAGLBSA-N
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| InChi Code |
InChI=1S/C20H20F6N8OS/c1-10-8-32(4-5-33(10)14(35)9-34-12(3)29-11(2)31-34)16-15(30-18(36-16)20(24,25)26)13-6-27-17(28-7-13)19(21,22)23/h6-7,10H,4-5,8-9H2,1-3H3/t10-/m1/s1
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| Chemical Name |
2-(3,5-dimethyl-1,2,4-triazol-1-yl)-1-[(2R)-2-methyl-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone
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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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 : ~110 mg/mL (~205.81 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8710 mL | 9.3549 mL | 18.7098 mL | |
| 5 mM | 0.3742 mL | 1.8710 mL | 3.7420 mL | |
| 10 mM | 0.1871 mL | 0.9355 mL | 1.8710 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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