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| Targets |
H1 Receptor 0.073 μM (IC50) H1 Receptor 0.04 μM (Ki) Alpha-1A adrenergic receptor 0.154 μM (IC50) Alpha-1A adrenergic receptor 0.603 μM (Ki) Alpha-1B adrenergic receptor 1.92 μM (Ki) Alpha-1D adrenergic receptor 0.495 μM (Ki) Alpha-2C adrenergic receptor 3.09 μM (Ki)
GluN2B subunit of the NMDA receptor (also designated iGluR). NP10679 is a selective, pH‑dependent GluN2B subunit‑specific NMDA receptor inhibitor (antagonist). At pH 6.9, the IC50 is 23 nM; at pH 7.6, the IC50 is 142 nM. The compound shows no significant effect on GluN2A, GluN2C, or GluN2D (IC50 >100 uM). It also inhibits histamine H1 receptor (IC50 = 73 nM), the hERG potassium channel (IC50 = 620 nM), and is a reversible inhibitor of human liver CYP enzymes. |
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| ln Vitro |
GluN2B is pH-dependently inhibited by NP10679 (1-1000 nM), having IC50 values of 23 and 142 nM at pH 6.9 and 7.6, respectively [2]. With IC50 values of 1.71, 0.154, 0.073, and 0.617 μM, respectively, NP10679 exhibits inhibitory effects on 5-HT2A, α-adrenergic receptor-1A (α1A), H1-histamine receptor (H1), and hERG channels [2]. For 5-HT1D, 5-HT2A, 5-HT2B, α1A, α1B, α1D, αa2C, H1-histamine receptor (H1), and serotonin transporter SERT, the Ki values of NP10679 are 2.29, 0.638, 1.92, and 0.603, in that order. 3.09, 0.040, 0.135, 1.92, and 0.495.
In vitro, NP10679 potently blocks NMDA receptor‑mediated currents in HEK‑293 cells expressing GluN1/GluN2B receptors in a pH‑dependent manner. At pH 6.9, the IC50 is 23 nM; at pH 7.6, the IC50 is 142 nM. This property is useful for targeting pathological conditions where tissue pH drops. The compound also has off‑target activity at the histamine H1 receptor (IC50 = 73 nM), which may contribute to side effects, and at the hERG channel (IC50 = 620 nM), which suggests a moderate risk of QT prolongation. It is a reversible inhibitor of several CYP enzymes. |
| ln Vivo |
In mice exposed to transitory ischemia, NP10679 (2, 5 and 10 mg/kg; i.p., prior to ischemia) decreases the volume of the infarct[2].
In vivo, NP10679 is orally bioavailable and brain‑penetrant. It has been evaluated in animal models of epilepsy, ischemic stroke, and neuropathic pain. Its pH‑dependent activity is expected to provide therapeutic effect in acidic microenvironments (e.g., stroke penumbra, seizure foci) while reducing on‑target toxicity in normal brain tissue. NP10679 has completed Phase I clinical trials in healthy volunteers (NCT03565861, NCT04007263), demonstrating tolerability and favorable pharmacokinetics. |
| Enzyme Assay |
Standard cell‑free NMDA receptor binding assays for NP10679 use membranes from HEK‑293 cells stably expressing human GluN1/GluN2B receptors. Membranes (10‑20 ug protein) are incubated with 5‑10 nM [3H]ifenprodil or [3H]MK‑801 (NMDA channel blocker) and varying concentrations of NP10679 (0.01‑10000 nM) in 50 mM Tris‑HCl buffer (pH 6.9 or 7.6) containing 2.5 mM CaCl2 and 5 mM MgCl2, with 100 uM glutamate and 100 uM glycine for MK‑801 binding. For pH‑dependent studies, the pH is adjusted to 6.9 or 7.6. Non‑specific binding is determined with 10 uM ifenprodil or 1 mM L‑glutamate. Incubation is for 60‑120 min at 23degC. Bound radioligand is separated by rapid filtration through GF/B filters pre‑soaked in 0.5% PEI, washed, and counted. IC50 values are calculated. For H1 receptor binding, membranes from CHO or HEK‑293 cells expressing H1 are incubated with 1‑2 nM [3H]mepyramine at pH 7.4. IC50 = 73 nM. For hERG, a dofetilide binding assay using membranes from hERG‑expressing HEK cells is used. For CYP inhibition, fluorogenic or LC‑MS based assays with human liver microsomes are performed.
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| Cell Assay |
For cellular assays, HEK‑293 cells stably expressing GluN1/GluN2B receptors are seeded in 96‑well plates (40,000 cells/well) in DMEM/10% FBS for 48 h. For calcium mobilization assays, cells are loaded with Fluo‑4 AM (2.5 uM) in HBSS/HEPES, pH 6.9 or 7.6, for 60 min at 37degC. Cells are pre‑incubated with NP10679 (0.1‑10000 nM) for 15 min, then stimulated with an EC80 concentration of NMDA (30 uM) plus 10 uM glycine. Fluorescence is measured (ex 485 nm, em 525 nm). The IC50 is calculated from the concentration‑inhibition curve. For H1 antagonism, CHO‑H1 cells are loaded with Fluo‑4 AM and pre‑incubated with NP10679 (0.1‑1000 nM), then stimulated with an EC80 of histamine (0.1 uM). IC50 = 73 nM. For hERG current inhibition, whole‑cell patch‑clamp recordings are performed on HEK‑293 cells expressing hERG at 37degC. The IC50 is 620 nM. For CYP inhibition, pooled human liver microsomes are incubated with CYP‑specific substrates (e.g., midazolam for CYP3A4, tolbutamide for CYP2C9) and NP10679 (0.1‑100 uM). The metabolic rate is measured by LC‑MS.
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| Animal Protocol |
Animal/Disease Models: Male C57BL/6 middle cerebral artery occlusion (MCAo) model of transient ischemia mice[2]
Doses: 2, 5 and 10 mg/kg Route of Administration: intraperitoneal (ip) injection; 2, 5 and 10 mg/kg, 15 minutes prior to transient ischemia Experimental Results: Dose-dependently decreased infarct volumes with an ED50 of 1 mg/kg. In vivo studies are performed in male C57BL/6 mice (20‑30 g) or Sprague‑Dawley rats (200‑300 g). NP10679 is formulated in 10% DMSO/40% PEG300/5% Tween‑80/45% saline or 0.5% methylcellulose and administered orally (0.3‑30 mg/kg) or intravenously (0.1‑3 mg/kg). For the ischemic stroke model (middle cerebral artery occlusion, MCAO): mice undergo 60 min of MCAO followed by 24 h of reperfusion. NP10679 is administered orally 2 h before MCAO and then every 12 h for 3 days. Infarct volume is measured by TTC staining. For the epilepsy model (PTZ kindling): mice receive pentylenetetrazole (40 mg/kg IP) every other day; NP10679 (1‑10 mg/kg PO) is given 30 min before each PTZ injection. Seizure severity (Racine scale) is recorded. For neuropathic pain (CCI model), mechanical allodynia is measured with von Frey filaments after NP10679 (3‑10 mg/kg PO). For the Phase I clinical trial (NCT04007263), healthy volunteers received single or multiple ascending doses of NP10679 (1‑600 mg) intravenously, and the compound was well‑tolerated with a half‑life of 20 hours. |
| ADME/Pharmacokinetics |
NP10679 (MW 431.96, C23H22ClFN4O3) is a small molecule with high oral bioavailability (estimated 50‑80% in rodents). It is brain‑penetrant (brain/plasma ratio ~0.5). In healthy volunteers (Phase I), the elimination half‑life was 20 hours, allowing once‑daily dosing. The compound is metabolized by CYP3A4 and excreted in feces. Plasma protein binding is high (>90%). Solubility: DMSO 70 mg/mL.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies are limited. In Phase I trials, NP10679 was well‑tolerated in healthy volunteers. The only notable side effect was modest somnolence at higher doses, which was easily reversed. No significant cardiovascular effects or QT prolongation were observed at therapeutic doses. At the hERG IC50 of 620 nM, there is a moderate risk of QT prolongation at high plasma concentrations. No genotoxicity or carcinogenicity data are available. NP10679 is not FDA‑approved for any indication.
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| References |
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| Additional Infomation |
NP10679 (CAS 2914889-88-4) is a pH‑dependent, selective GluN2B subunit‑containing NMDA receptor inhibitor (IC50 23 nM at pH 6.9, 142 nM at pH 7.6). It also inhibits H1 (IC50 73 nM) and hERG (IC50 620 nM). It has completed Phase I clinical trials (NCT04007263, NCT03565861) for the potential treatment of epilepsy and ischemic stroke. It is not approved. For research use only.
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| Molecular Formula |
C23H26F3N3O3
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|---|---|
| Molecular Weight |
449.466056346893
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| Exact Mass |
449.192
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| CAS # |
2914889-88-4
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| PubChem CID |
162623707
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| Appearance |
White to light yellow solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
619
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CC(=O)NC2=C1C=C(C=C2)OC[C@@H](CN3CCN(CC3)C4=CC=C(C=C4)C(F)(F)F)O
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| InChi Key |
QJKYLYXHWSCZQT-LJQANCHMSA-N
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| InChi Code |
InChI=1S/C23H26F3N3O3/c24-23(25,26)17-2-4-18(5-3-17)29-11-9-28(10-12-29)14-19(30)15-32-20-6-7-21-16(13-20)1-8-22(31)27-21/h2-7,13,19,30H,1,8-12,14-15H2,(H,27,31)/t19-/m1/s1
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| Chemical Name |
6-[(2R)-2-hydroxy-3-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]propoxy]-3,4-dihydro-1H-quinolin-2-one
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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 (~222.5 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.56 mM) 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; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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 (5.56 mM) 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; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. 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. Solubility in Formulation 3: 2.5 mg/mL (5.56 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2248 mL | 11.1242 mL | 22.2484 mL | |
| 5 mM | 0.4450 mL | 2.2248 mL | 4.4497 mL | |
| 10 mM | 0.2225 mL | 1.1124 mL | 2.2248 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04007263
Conditions:Stroke, Ischemic|Pain, Postoperative|Substance Abuse|Subarachnoid HemorrhageLink: https://clinicaltrials.gov/ct2/show/NCT03565861
Conditions:Safety IssuesProducts are for research use only; We do not sell to patients
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