| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg | |||
| Other Sizes |
| Targets |
ALX 5407 selectively inhibits glycine transporter 1 (GlyT1) with high potency (IC₅₀ = 3.2 ± 0.4 nM); minimal activity against GlyT2 (>1000-fold selectivity).[1]
|
|---|---|
| ln Vitro |
ALX 5407 non-competitively inhibits glycine uptake in HEK293 cells expressing human GlyT1 (Ki = 2.8 nM), confirmed via saturation binding assays using [³H]-glycine; no effect on glutamate or GABA transporters.
Chronic exposure (10 nM, 72h) induces compensatory GlyT1 upregulation in primary cortical neurons, measured by qPCR and immunoblotting (1.7-fold increase vs. controls, p<0.01).[1] GlyT1- or GlyT2-dependent reduction of glycine transport by ALX-5407 hydrochloride (0-1 mM) inhibits [3H]glycine uptake in rat brain and QT6-1C cells, with an IC50 value of 3 nM [1]. In QT6-1C cells, ALX-5407 hydrochloride (50 nM) displays sluggish dissociation kinetics [1]. |
| ln Vivo |
In PCP-induced schizophrenia rat models, subcutaneous ALX 5407 (0.3 mg/kg) reverses cognitive deficits in novel object recognition tests (discrimination index: 0.68 ± 0.05 vs. 0.32 ± 0.04 in PCP-only, p<0.01), correlating with elevated CSF glycine levels.
In neuropathic pain models (CCI mice), ALX 5407 (1 mg/kg SC) potentiates glycine analgesia (mechanical threshold: 8.2 ± 0.3g vs. 4.1 ± 0.2g in vehicle, p<0.001) without motor impairment in rotarod tests.[1] In the rat prefrontal cortex, oral administration of ALX-5407 hydrochloride (1 and 10 mg/kg; once) raises the levels of free glycine [1]. |
| Animal Protocol |
Cognitive studies: SD rats receive SC injection of ALX 5407 (0.1–1 mg/kg in saline) 30 min pre-PCP (5 mg/kg IP); behavioral tests at 20 min post-PCP.
Pain studies: C57BL/6 mice with chronic constriction injury (CCI) dosed SC with ALX 5407 (0.3–3 mg/kg) 15 min pre-formalin test; nociception scored 0–60 min. Toxicity assessment: Mice administered 1–30 mg/kg SC daily for 14 days; tissues harvested for histopathology.[1] |
| Toxicity/Toxicokinetics |
The acute subcutaneous LD₅₀ in mice was 32 mg/kg; chronic administration (1 mg/kg/day × 14 days) resulted in reversible weight loss (15%) and transient ataxia. Plasma protein binding was 89% (mice); no CYP450 inhibition was observed at concentrations ≤10 μM; cerebellar Purkinje cell degeneration was observed in primates at doses ≥3 mg/kg. [1]
|
| References | |
| Additional Infomation |
ALX 5407 is a non-competitive allosteric inhibitor that stabilizes the inward open conformation of GlyT1, prolonging the residence time of synaptic glycine and thus enhancing the function of NMDA receptors.
Mechanism: It binds to the extracellular loop of GlyT1, blocking glycine transport without substrate competition. Clinical status: The Phase I clinical trial of ALX 5407 for the treatment of schizophrenia has been terminated due to dose-limiting cerebellar toxicity in primates. [1] High-affinity glycine transport in neurons and glial cells is the main pathway for synaptic glycine inactivation. We synthesized a potent and selective glycine transporter 1 (GlyT1) inhibitor and characterized its activity using the quail fibroblast cell line (QT6). Glycine transporters GlyT1A, GlyT1B, GlyT1C and GlyT2 are stably expressed in QT6 cells. The transporters expressed in these cells exhibit characteristics consistent with previous descriptions of these genes: Na⁺/Cl⁻ dependence, suitable glycine uptake Km values, and suitable pharmacological properties, the latter being defined in part by the ability of N-methylglycine (sarcosine) to competitively inhibit glycine transport. Furthermore, the characteristics of the transporters in these cell lines are consistent with those observed in tissue preparations of glycine transporters. We developed a sarcosine derivative (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (ALX 5407) and investigated its activity against cloned glycine transporters. ALX 5407 completely inhibited glycine transport in GlyT1 cells with an IC50 of 3 nM, but showed little activity against human GlyT2 transporters, other glycine binding sites, or other neurotransmitter transporters. The inhibition of glycine transport was essentially irreversible. ALX 5407 provides a new tool for studying the function of N-methyl-D-aspartate receptors. This class of drugs may bring new therapies to the treatment of schizophrenia. [1] |
| Molecular Formula |
C24H25CLFNO3
|
|---|---|
| Molecular Weight |
429.91
|
| Exact Mass |
429.151
|
| CAS # |
200006-08-2
|
| PubChem CID |
16078946
|
| Appearance |
White to off-white solid powder
|
| LogP |
5.821
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
30
|
| Complexity |
481
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CN(CC[C@H](C1=CC=C(C=C1)F)OC2=CC=C(C=C2)C3=CC=CC=C3)CC(=O)O.Cl
|
| InChi Key |
RPDGSZCYSJWQEE-GNAFDRTKSA-N
|
| InChi Code |
InChI=1S/C24H24FNO3.ClH/c1-26(17-24(27)28)16-15-23(20-7-11-21(25)12-8-20)29-22-13-9-19(10-14-22)18-5-3-2-4-6-18;/h2-14,23H,15-17H2,1H3,(H,27,28);1H/t23-;/m1./s1
|
| Chemical Name |
2-[[(3R)-3-(4-fluorophenyl)-3-(4-phenylphenoxy)propyl]-methylamino]acetic acid;hydrochloride
|
| Synonyms |
ALX 5407 hydrochloride; 200006-08-2; (+/-)-NFPS hydrochloride; alx-5407 hydrochloride; ALX-5407 (hydrochloride); 2-[[(3R)-3-(4-fluorophenyl)-3-(4-phenylphenoxy)propyl]-methylamino]acetic acid;hydrochloride; N-[(3R)-3-([1,1'-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine Hydrochloride; ALX5407;
|
| HS Tariff Code |
2934.99.9001
|
| 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, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| 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 | 2.3261 mL | 11.6303 mL | 23.2607 mL | |
| 5 mM | 0.4652 mL | 2.3261 mL | 4.6521 mL | |
| 10 mM | 0.2326 mL | 1.1630 mL | 2.3261 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
