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Purity: ≥98%
Apimostinel (NRX-1074; AGN-241660) is a novel and orally bioactive antidepressant which acts as a selective partial agonist of an allosteric site of the glycine site of the NMDA receptor complex, which is under investigation by Naurex (recently acquired by Allergan) for the treatment of major depressive disorder. Its mechanism of action and effects are similar to those of rapastinel (GLYX-13), which is under development as an adjunctive therapy for treatment-resistant depression also by Naurex; however, NRX-1074 is 100-fold more potent by weight and, unlike GLYX-13 (which must be administered via intravenous injection), is orally -active.
| Targets |
NMDA receptor
|
|---|---|
| ln Vitro |
Similar to GLYX-13, apimostinel (NRX-1074) regulates NMDA receptors; however, because it is a synthetic modification of one of the amino acids, it has a higher efficacy and oral bioavailability [1].
|
| ln Vivo |
In preclinical models, both drugs appear to be particularly effective against a range of central nervous system illnesses [1].
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| ADME/Pharmacokinetics |
Apimostinel (NRX-1074/AGN-241751) is a higher-potency rapastinel analog with increased bioavailability.
NRX-1074 modulates the NMDA receptor in a similar fashion to GLYX-13, but has a synthetic modification to one of the amino acids, conferring increased potency and oral bioavailability |
| References | |
| Additional Infomation |
NRX-1074 has been used in trials studying the treatment of Schizophrenia.
Naurex reported today that the first efficacy trial for NRX-1074, using a single-dose IV administration of a compound that will be delivered orally from now on, established a remarkable degree of immediate impact. At 24 hours post-injection of the highest dose (and unlike GlyX-13, NRX-1074 does not have an inverted-U doseresponse curve), the mean reductionin Hamilton scores was 14 points, the effect size was .88. The effect size itself, just 24 hours later, is impressive compared to current antidepressants. It was also pleasantly surprising that 72% of patients receiving NRX-1074 showed a ‘clinically meaningful’ response, given that in rapastinel/GlyX13’s PhIIb, only about half of the patients appeared to be treatment responsive. The usual caveats--small treatment samples for each of the three doses, 35 patients; just a single-dose readout; IV delivery of this oral compound--do apply, and the data release did not offer anything regarding the durability of the antidepressant response. However, durability is far less important here than it was with IV GlyX-13, for which minimizing the frequency of re-infusion would be an important treatment consideration. These data at 24 hours suggest that once-daily administration would be viable, the sweet spot for an oral antidepressant. The next clinical step (starting this spring) will be a repeated-dose, oral administration trial of NRX-1074, as monotherapy-- in contrast to GlyX-13, being developed as an adjunct. As to the next corporate development step, it seems a near-certainty that Naurex will go the IPO route to funding their ambitious clinical development agenda--the question to us is not whether, but when.[1] |
| Molecular Formula |
C25H37N5O6
|
|---|---|
| Molecular Weight |
503.59
|
| Exact Mass |
503.274
|
| Elemental Analysis |
C, 59.63; H, 7.41; N, 13.91; O, 19.06
|
| CAS # |
1421866-48-9
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| Related CAS # |
1421866-48-9;
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| PubChem CID |
71249967
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
878.7±65.0 °C at 760 mmHg
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| Flash Point |
485.2±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.608
|
| LogP |
0.22
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| Hydrogen Bond Donor Count |
5
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
36
|
| Complexity |
834
|
| Defined Atom Stereocenter Count |
6
|
| SMILES |
O=C([C@@H]1CCCN1C([C@H]([C@@H](C)O)N)=O)N1CCC[C@]1(C(N[C@H](C(N)=O)[C@@H](C)O)=O)CC1C=CC=CC=1
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| InChi Key |
DVBUEXCIEIAXPM-PJUQSVSOSA-N
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| InChi Code |
InChI=1S/C25H37N5O6/c1-15(31)19(26)23(35)29-12-6-10-18(29)22(34)30-13-7-11-25(30,14-17-8-4-3-5-9-17)24(36)28-20(16(2)32)21(27)33/h3-5,8-9,15-16,18-20,31-32H,6-7,10-14,26H2,1-2H3,(H2,27,33)(H,28,36)/t15-,16-,18+,19+,20+,25-/m1/s1
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| Chemical Name |
(2R)-1-[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-2-benzylpyrrolidine-2-carboxamide
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| Synonyms |
NRX-1074; NRX 1074; Apimostinel; NRX-1074; Apimostinel [USAN]; UNII-TTT1F11FZB; Apimostinel (USAN); NRX1,074; APIMOSTINEL [INN]; ...; 1421866-48-9; NRX1074; AGN-241660; AGN241660; AGN 241660.
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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. |
| 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 : ~155 mg/mL (~307.79 mM)
H2O : ≥ 6.67 mg/mL (~13.24 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7.75 mg/mL (15.39 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 77.5 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: ≥ 7.75 mg/mL (15.39 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 77.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9857 mL | 9.9287 mL | 19.8574 mL | |
| 5 mM | 0.3971 mL | 1.9857 mL | 3.9715 mL | |
| 10 mM | 0.1986 mL | 0.9929 mL | 1.9857 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06400121 | NOT YET RECRUITING | Drug: Apimostinel Infusion, Intravenous Behavioral: Cognitive Training Behavioral: Sham Training Drug: Lactated Ringers, Intravenous |
Depression | Rebecca Price | 2024-09-01 | Phase 2 |
| NCT05597241 | COMPLETED | Drug: apimostinel Drug: Placebo |
Major Depressive Disorder | Gate Neurosciences, Inc | 2022-10-15 | Phase 1 |
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