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Purity: ≥98%
Rislenemdaz (also known as MK-065; CERC-301) is a novel, potent, orally bioavailable and selective antagonist of the N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) with Ki and IC50 of 8.1 nM and 3.6 nM, respectively. It has the potential for the treatment of Parkinson's disease. In the preclinical pharmacological and pharmacokinetic study, CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.6 nmol L(-1) and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 of 2 mg kg(-1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L(-1), similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L(-1), respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with T max of ~1 h and t 1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.
| ln Vitro |
For agonist-stimulated NMDA-GluN1a/GluN2BL(tk-) cells, rislenemdaz (CERC-301) reduces calcium influx with an IC50 of 3.6 nM. When GluN2B receptors are compared to all other targets, including hERG potassium channels, rislenemdaz exhibits a minimum of 1000-fold selectivity. Minimal action of rislenemdaz against sigma-type receptors is also shown at 10 uM [1].
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| ln Vivo |
In comparison with vehicle control, rislenemdaz (CERC-301) (1, 3, 10 and 30 mg/kg) significantly improved swimming behavior (P<0.05 at 10 mg/kg; P<0.01 for 1, 3 and 30 mg/kg) and greatly decreased the frequency of immobility (P<0.001). Rats had plasma levels of rislenemdaz of about 15, 120, 390, 1420, 4700, and 14,110 nM (0.015, 0.120, 0.390, 1.42, 4.7, and 14.11 uM) at the time of sampling. This is equivalent to about 5, 29, 56, 83, and 94% and 98% RO, respectively. About 0.3 and 0.7 mg/kg, or roughly 30% and 50% of RO, are the estimated ED50s for increasing swimming frequency and reducing immobility, respectively. Comparing the total distance traveled with the vehicle control (1 mg/kg P < 0.01; 3, 10, and 30 mg/kg P < 0.001), rislenemdaz (1, 3, 10, and 30 mg/kg) significantly increased the distance traveled. Little to no testing [1].
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| References | |
| Additional Infomation |
Mk 0657 has been used in trials studying the treatment of Major Depressive Disorder.
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| Molecular Formula |
C19H23FN4O2
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|---|---|
| Molecular Weight |
358.409927606583
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| Exact Mass |
358.18
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| CAS # |
808732-98-1
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| Related CAS # |
808733-06-4 (HCl);808732-98-1;1893392-76-1 (mesylate);
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| PubChem CID |
11394238
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
527.4±60.0 °C at 760 mmHg
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| Flash Point |
272.7±32.9 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.584
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| LogP |
2.73
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
439
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC1=CC=C(C=C1)COC(=O)N2CC[C@@H]([C@@H](C2)F)CNC3=NC=CC=N3
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| InChi Key |
RECBFDWSXWAXHY-IAGOWNOFSA-N
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| InChi Code |
InChI=1S/C19H23FN4O2/c1-14-3-5-15(6-4-14)13-26-19(25)24-10-7-16(17(20)12-24)11-23-18-21-8-2-9-22-18/h2-6,8-9,16-17H,7,10-13H2,1H3,(H,21,22,23)/t16-,17-/m1/s1
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| Chemical Name |
4-methylbenzyl (3S,4R)-3-fluoro-4-((pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate
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| Synonyms |
CERC-301; CERC301; CERC 301; MK-0657; MK 0657; MK0657;
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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 (~279.01 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.98 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 25.0 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: ≥ 2.5 mg/mL (6.98 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 25.0 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: ≥ 2.5 mg/mL (6.98 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 | 2.7901 mL | 13.9505 mL | 27.9010 mL | |
| 5 mM | 0.5580 mL | 2.7901 mL | 5.5802 mL | |
| 10 mM | 0.2790 mL | 1.3951 mL | 2.7901 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.
(A) Time course ofN‐methyl‐D‐aspartate (NMDA) receptor inhibition by CERC‐301 at three concentrations of 30, 100, and 300nmolL−1.Pharmacol Res Perspect. 2015 Dec; 3(6): e00198. |
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In‐vivo efficacy and potential central nervous system (CNS) side effects of CERC‐301 when orally administered in rats. Efficacy is depicted by a reduction in immobility frequency (filled circles; left axis) during the forced swim test. Potential CNS side effect is depicted by an increase in total distance traveled (open squares; right axis) as a function of dose.Pharmacol Res Perspect. 2015 Dec; 3(6): e00198. |
Effects of a single oral dose ofCERC‐301 on systolic blood pressure.Pharmacol Res Perspect. 2015 Dec; 3(6): e00198. |
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