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Purity: ≥98%
JNJ-54175446 (JNJ54175446) is a novel, potent and selective brain penetrant P2X7 receptor antagonist being developed for treating major depressive disorder. It inhibits hP2X7 receptor and rP2X7 receptor with pIC50s of 8.46 and 8.81, respectively. JNJ-5417544 has suitable physicochemical properties, metabolic stability and an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. JNJ-54175446 has been advanced as a candidate to clinical development.
JNJ-54175446 is a potent, selective, and orally bioavailable small-molecule antagonist of the purinergic P2X7 receptor, designed to penetrate the central nervous system (CNS). It is a 4-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine derivative with high permeability (Caco-2 Papp = 75.3 × 10⁻⁶ cm/s) and excellent metabolic stability across species (human liver microsome extraction ratio <0.3). In vivo, JNJ-54175446 achieves high brain exposure and has demonstrated robust target engagement. In a mouse model of drug-resistant temporal lobe epilepsy (intra-amygdala kainic acid), once-daily oral dosing (30 mg/kg) significantly reduced spontaneous recurrent seizures and attenuated astrogliosis. In patients with major depressive disorder (MDD), JNJ-54175446 (600 mg loading then 150 mg/day) was well-tolerated and reduced ex vivo IL-1β release, confirming target engagement, while blunting total sleep deprivation-induced reduction in anhedonia, suggesting potential mood-stabilizing effects. Its predicted human half-life is 29 hours with an estimated efficacious dose of 8 mg once daily.| Targets |
P2X7 receptor – selective purine P2X7 receptor antagonist; EC50 for P2X7 receptor occupancy in rat brain: plasma concentration of 105 ng/mL (EC50), >80% occupancy occurs above 1000 ng/mL [1][2][3]
pIC50: 8.46 (hP2X7 receptor), 8.81 (rP2X7 receptor)[1] |
|---|---|
| ln Vitro |
In Vitro: JNJ-54175446 is a potent, selective, and brain-penetrant P2X7 receptor antagonist. It is highly permeable with no evidence of efflux as measured by Caco-2 cell line (A to B Papp = 75.3 × 10⁻⁶ cm⁻¹/sec, B to A Papp = 37.1 × 10⁻⁶ cm⁻¹/sec). [1]
JNJ-54175446 demonstrated excellent metabolic stability in liver microsomes across species: human extraction ratio <0.3, rat <0.2, dog <0.25, cynomolgus monkey <0.26, mouse <0.25. [1] JNJ-54175446 showed no significant activity in a panel of 50 ion channels, receptors, and transporters (tested at 10 μM), a kinase panel (tested at 1 μM), and related P2X receptors (P2X1, P2X2, P2X3, P2X2/3, P2X4 FLIPR assays, tested up to 10 μM). [1] JNJ-54175446 had no significant hERG binding (IC50 > 10 μM). [1] Protein binding: rat PPB 87.8%, human PPB 88.8%, mouse PPB 88.7%, rat brain binding 94.9%. Solubility: 38.7 μM at pH 2, 20.7 μM at pH 7. [1] Compound 14, also known as JNJ-54175446, is a strong and specific brain penetrant P2X7 antagonist. Its pIC50s for hP2X7 and rP2X7 are 8.46 and 8.81, respectively. In comparison to mouse, dog, and macaque P2X7 (pIC50, 7.8, 7.9, and 8.1, respectively), JNJ-54175446 exhibits less strong activity[1]. |
| ln Vivo |
In Vivo: In the intra-amygdala kainic acid mouse model of drug-resistant temporal lobe epilepsy, once-daily intraperitoneal dosing of JNJ-54175446 (30 mg/kg for 5 days) resulted in a significant reduction in spontaneous recurrent seizures during the post-treatment washout period (p = 0.022). Seizure rates in vehicle-treated mice averaged ~10 per day, while JNJ-54175446-treated mice had significantly lower seizure frequency. No effect on seizure duration was observed. [2]
JNJ-54175446 (30 mg/kg, i.p., 5 days) reduced astrogliosis (GFAP staining) in the ipsilateral CA3 subfield of the hippocampus in epileptic mice, but did not significantly alter microgliosis (IBA1 staining). IBA1-positive microglia in JNJ-54175446-treated mice displayed higher numbers of endpoints and longer process lengths compared to vehicle-treated mice. [2] In MDD patients, JNJ-54175446 (600 mg loading dose on day 1 followed by 150 mg once daily for 10 days) was well tolerated. It reduced IL-1β release by LPS-stimulated peripheral white blood cells in the presence of the P2X7 receptor agonist BzATP, demonstrating proof of pharmacological activity. [3] JNJ-54175446 did not have a significant effect on mood as assessed using HDRS17 and QIDS-SR in MDD patients. However, it blunted the acute reduction of anhedonia that occurred as a result of total sleep deprivation, as assessed by SHAPS (group A vs placebo, p = 0.049) and PILT total amount lost (non-significant trend). [3] Ex vivo autoradiography using ¹⁸F-JNJ-64413739 showed no significant difference in P2X7 receptor binding between vehicle- and JNJ-54175446-treated epileptic mice at the end of recordings (2 weeks after drug washout). [2] The ED50 of JNJ-54175446 is 0.46 mg/kg, which is equivalent to a plasma EC50 of 105 ng/mL. This indicates dose-dependent occupancy[1]. |
| Enzyme Assay |
Enzyme Assay: P2X7 calcium flux FLIPR assay: 1321N1 cells expressing recombinant P2X7 channel were seeded at 25,000 cells/well in 96-well plates. Cells were loaded with Calcium-4 dye and incubated for 60 min. Test compounds were prepared in assay buffer. Cells were incubated with test compounds for 30 min. BzATP was added and fluorescence change measured for 180 seconds. [1]
P2X7 radioligand binding assay: Cell membrane preparations from recombinant P2X7 1321N1 cells were incubated with [³H]-A-804598 tracer and test compounds for 1 hour at 4°C. The assay was terminated by filtration. IC50 was corrected for tracer concentration and affinity. [1] Plasma protein binding by equilibrium dialysis: Compounds were spiked into plasma at 1 μM. Dialysis was performed using RED device with 8 kDa-permeable cellulose membrane for 6 h at 37°C. Samples were analyzed by LC/MS/MS. [1] Liver microsomal stability: Test compounds (1 μM) were incubated with liver microsomes (0.5 mg/mL) and NADPH (1 mM). Aliquots were taken at 0, 5, 10, 20, 40, 60 min and quenched. Half-lives were derived and hepatic extraction ratios calculated. [1] CYP inhibition cocktail assay: Human liver microsomes were incubated with six CYP substrates (phenacetin for CYP1A2, paclitaxel for CYP2C8, diclofenac for CYP2C9, S-mephenytoin for CYP2C19, dextromethorphan for CYP2D6, midazolam for CYP3A) and test compounds. Probe metabolite formation was analyzed by LC-MS/MS. [1] |
| Cell Assay |
Cell Assay: Caco-2 permeability assay: Caco-2 cells were seeded onto 96-well plates and cultured for at least 21 days. Test compounds (10 μM) were applied to donor side and incubated at 37°C for 60 min (A→B) or 40 min (B→A). Apparent permeability coefficient (Papp) was calculated. [1]
1321N1 cells expressing recombinant P2X7 channel were cultured in HyQ DME high glucose with 10% FBS and selection marker. Cells were seeded at 25,000 cells/well for calcium flux assays. [1] |
| Animal Protocol |
Animal Protocol: Intra-amygdala kainic acid (IAKA) mouse model of temporal lobe epilepsy: Male C57BL/6JOlaHsd mice (25-30 g, 10 weeks old) were anesthetized with isoflurane. An EEG transmitter was implanted subcutaneously. A guide cannula was placed above the right basolateral amygdala. After 48 h recovery, KA (0.3 μg in 0.2 μL) was microinjected. Status epilepticus was recorded. After 40 min, lorazepam (8 mg/kg, i.p.) was given to reduce mortality. JNJ-54175446 (30 mg/kg, i.p., once daily for 5 days) or vehicle was administered starting 14 days after KA. Dosing was then terminated and seizures recorded for another 13 days. Mice were perfused transcardially with PBS and brains collected for histology. [2]
MDD patient study (NCT02902601): Male and female MDD patients (18-64 years) with IDS-C30 ≥ 30 were randomized to: Group A (JNJ-54175446 throughout: 600 mg loading day 1, then 150 mg q.d. days 2-10), Group B (placebo days 1-3, then 600 mg day 4 loading, 150 mg q.d. days 5-10), or Group C (placebo throughout). All patients underwent 36 h total sleep deprivation from day 3 to day 4, with light therapy (10,000 lux, 30 min) at 03:00 during and 08:00 following sleep deprivation. [3] |
| ADME/Pharmacokinetics |
ADME/Pharmacokinetics: In rats, JNJ-54175446 (1 mg/kg i.v., 5 mg/kg p.o.) showed: CL = 2.9 mL/min/kg, Vss = 2.1 L/kg, t1/2 = 8.6 h, F = 96%. [1]
In dogs: CL = 0.9 mL/min/kg, Vss = 2.5 L/kg, t1/2 = 32 h, F = 164%. [1] In NHP: CL = 4.4 mL/min/kg, Vss = 2.1 L/kg, t1/2 = 6.9 h, F = 157%. [1] In MDD patients, following a single 600 mg dose: Cmax = 1181 ± 394 ng/mL, tmax median 7.98 h (range 3.93-23.33 h), AUCt = 21107 ± 6841 ng·h/mL. Following multiple doses of 150 mg q.d. on day 10: Cmax = 1932 ± 664 ng/mL, Cmin = 1417 ± 510 ng/mL, Cavg = 1671 ± 591 ng/mL, tmax median 4.00 h (2.00-10.00 h), AUCt = 39905 ± 14069 ng·h/mL, terminal t1/2 = 50.2 ± 17.8 h. Accumulation ratio: AUCt on day 10 approximately 1.9-fold higher than day 1. [3] Human PK prediction from allometry: predicted CL 0.6 mL/min/kg, Vss 1.4 L/kg, t1/2 29 h. Estimated dose to maintain >50% occupancy over 24 h: 8 mg q.d. (assuming 100% bioavailability). [1] |
| Toxicity/Toxicokinetics |
Toxicity/Toxicokinetics: In a 4-day rat toleration study at doses of 62.5, 125, and 250 mg/kg, no significant clinical observations were noted and exposures were high at all doses. [1]
In a 5-day dog toleration study at doses of 30, 100, and 300 mg/kg, exposures were high and no relevant changes in serum chemistry, necropsy, or histopathology were observed. [1] In MDD patients, JNJ-54175446 was well-tolerated. The most common treatment-emergent adverse events in patients receiving JNJ-54175446 were headache (25.0%), nausea (11.5%), dysgeusia (5.8%), and vomiting (5.8%). All adverse events were mild to moderate. No deaths, serious AEs, or persistent AEs were reported. No clinically significant changes in laboratory evaluations, vital signs, or ECG parameters were observed. [3] |
| References |
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| Additional Infomation |
JNJ-54175446 ((R)-(2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-4-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone) is a potent, selective, brain-penetrant P2X7 receptor antagonist. The absolute configuration was determined by X-ray crystallography as (R). The compound has high permeability (Caco-2 A to B Papp = 75.3 × 10⁻⁶ cm⁻¹/sec) and no efflux. It has a cLogP of 3.00, molecular weight 440.8. The compound was nominated for clinical development and has been dosed in healthy volunteers at single doses from 0.5 mg to 600 mg, all well tolerated. [1] In the IAKA model, JNJ-54175446 reduced spontaneous seizures and gliosis, supporting P2X7 receptor antagonism as a potential therapeutic approach for drug-resistant temporal lobe epilepsy. [2] In MDD patients, JNJ-54175446 blunted TSD-induced reduction in anhedonia, suggesting potential mood-stabilizing effects on hedonic capacity. [3]
JNJ-54175446 is being studied in the clinical trial NCT02933762 (a study evaluating the effects of JNJ-54175446 on amyloid biomarkers and cytokine profiles in cerebrospinal fluid and plasma in healthy participants). |
| Molecular Formula |
C18H13CLF4N6O
|
|---|---|
| Molecular Weight |
440.782035589218
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| Exact Mass |
440.077
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| Elemental Analysis |
C, 49.05; H, 2.97; Cl, 8.04; F, 17.24; N, 19.07; O, 3.63
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| CAS # |
1627902-21-9
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| PubChem CID |
90409366
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| Appearance |
Light yellow to yellow solid powder
|
| LogP |
3
|
| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
9
|
| Rotatable Bond Count |
2
|
| Heavy Atom Count |
30
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| Complexity |
634
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1C(C(F)(F)F)=CC=CC=1C(N1CCC2=C([C@H]1C)N=NN2C1N=CC(=CN=1)F)=O
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| InChi Key |
CWFVVQFVGMFTBD-SECBINFHSA-N
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| InChi Code |
InChI=1S/C18H13ClF4N6O/c1-9-15-13(29(27-26-15)17-24-7-10(20)8-25-17)5-6-28(9)16(30)11-3-2-4-12(14(11)19)18(21,22)23/h2-4,7-9H,5-6H2,1H3/t9-/m1/s1
|
| Chemical Name |
(R)-(2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-4-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone
|
| Synonyms |
JNJ54175446; JNJ 54175446; JNJ-54175,446; 32524GLF40; Methanone, (2-chloro-3-(trifluoromethyl)phenyl)((4R)-1-(5-fluoro-2-pyrimidinyl)-1,4,6,7-tetrahydro-4-methyl-5H-1,2,3-triazolo(4,5-C)pyridin-5-yl)-; Methanone, (2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoro-2-pyrimidinyl)-1,4,6,7-tetrahydro-4-methyl-5H-1,2,3-triazolo(4,5-c)pyridin-5-yl)-; 1627902-21-9; JNJ-54175446
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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 : ~62.5 mg/mL (~141.79 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.72 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 (4.72 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 20.8 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: ≥ 2.08 mg/mL (4.72 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 | 2.2687 mL | 11.3435 mL | 22.6871 mL | |
| 5 mM | 0.4537 mL | 2.2687 mL | 4.5374 mL | |
| 10 mM | 0.2269 mL | 1.1344 mL | 2.2687 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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