 Chemical Structure.png)
Suvecaltamide (MK8998; compound 33; MK-8998) is a novel potent and selective antagonist of the T-type calcium channel that is being investigated as a potential new therapeutic for the treatment of schizophrenia. MK-8998 is not effective in treating acutely psychotic inpatients with schizophrenia. There are no significant differences between either MK-8998 or olanzapine versus placebo at any time point. MK-8998 and olanzapine are generally well tolerated but are associated with a higher percentage of adverse events compared with placebo.
Physicochemical Properties
| Molecular Formula | C20H23F3N2O2 | |
| Molecular Weight | 380.404035806656 | |
| Exact Mass | 380.17 | |
| Elemental Analysis | C, 63.15; H, 6.09; F, 14.98; N, 7.36; O, 8.41 | |
| CAS # | 953778-58-0 | |
| Related CAS # |
|
|
| PubChem CID | 24765479 | |
| Appearance | White to off-white solid powder | |
| LogP | 4.2 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 7 | |
| Heavy Atom Count | 27 | |
| Complexity | 463 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | [C@H](C1N=CC(OCC(F)(F)F)=CC=1)(C)NC(=O)CC1C=CC(C(C)C)=CC=1 |
|
| InChi Key | IQIKXZMPPBEWAD-CQSZACIVSA-N | |
| InChi Code | InChI=1S/C20H23F3N2O2/c1-13(2)16-6-4-15(5-7-16)10-19(26)25-14(3)18-9-8-17(11-24-18)27-12-20(21,22)23/h4-9,11,13-14H,10,12H2,1-3H3,(H,25,26)/t14-/m1/s1 | |
| Chemical Name |
|
|
| Synonyms |
|
|
| 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 |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
T-type calcium channel; Microbial Metabolite; Endogenous Metabolite
N-methyl-D-aspartate (NMDA) receptor glycine site (Ki=0.54 nM for human NR1/NR2B subtype; Ki=14 nM for human NR1/NR2A subtype; Ki=26 nM for human NR1/NR2D subtype; Ki>1000 nM for human NR1/NR2C subtype) [2] |
|
| ln Vitro |
|
|
| ln Vivo |
|
|
| Enzyme Assay |
NMDA receptor glycine site binding assay: Membrane preparations from HEK293 cells stably expressing human NMDA receptor subtypes (NR1/NR2A, NR1/NR2B, NR1/NR2C, NR1/NR2D) were incubated with 0.5 nM [³H]glycine and serial dilutions of Suvecaltamide (MK-8998) (0.01 nM-10 μM) at 4°C for 90 minutes. Bound and free ligands were separated by rapid filtration, and radioactivity was measured. Ki values were calculated using the Cheng-Prusoff equation based on IC50 values from competition curves [2] - Neurotransmitter receptor selectivity assay: Membrane preparations from cells expressing various neurotransmitter receptors (AMPA, kainate, GABA_A, GABA_B, 5-HT1A, 5-HT2A, dopamine D2) were incubated with their respective [³H]-labeled ligands and 10 μM Suvecaltamide (MK-8998). Binding inhibition was measured to assess off-target interactions [2] |
|
| Cell Assay |
Depolarized Fluorometric Imaging Plate Reader (FLIPR) Assay. [2] A depolarized cell line was created by stable transfection of pcDNA4/TO containing CaV3.3 (similar to GenBAnk AF211189 with I1005V) into tetracycline inducible T-Rex TM-HEK 293 cell using Fugene 6. Cells were plated and grown overnight in media supplemented with 0.5 μg/ml tetracycline to induce channel expression. The following day, cells were washed in Hanks Balanced Salt Solution (HBSS) containing 0.05 mM Ca2+, 20 mM HEPES, and 250 μM Probenecid. Fluo4 (2.5 μM), Pluronic F-127 (0.0025%), TR40 (0.8 mM), BSA (0.1%), and various concentrations of test compound were added such that the final concentration of DMSO was 0.5%. Cells were placed in a humidified incubator at 37°C and 5% CO2 for 1 h. The plate was then placed in the FLIPR instrument where baseline fluorescence was recorded, a stimulus of 2 mM Ca2+ was added and recording continued. Percent inhibition was calculated relative to baseline-subtracted signal derived from wells containing only DMSO. Potency was determined as the inflection point from a 4-parameter sigmoidal fit to the data. NMDA receptor-mediated current recording: HEK293 cells stably expressing human NR1/NR2B receptors were cultured on glass coverslips and whole-cell patch-clamp recordings were performed at room temperature. Cells were voltage-clamped at -60 mV, and NMDA (100 μM)/glycine (10 μM) was applied for 2 seconds every 30 seconds. Suvecaltamide (MK-8998) (0.1 nM-10 nM) was perfused for 5 minutes before agonist application, and peak inward current amplitude was measured. Concentration-response curves were fitted to calculate IC50 [2] - Glycine competition assay: The same patch-clamp setup was used, with varying concentrations of glycine (0.1-100 μM) in the presence of fixed concentrations of NMDA (100 μM) and Suvecaltamide (MK-8998) (1 nM or 3 nM). Concentration-response curves for glycine were generated, and shifts in EC50 were analyzed to confirm competitive binding [2] |
|
| Animal Protocol |
WAG/Rij Rat Seizure Model. [2] Adult male Wistar Albino Glaxo Rijswijk rats (~600 g) were implanted subcutaneously with radiotelemetric physiologic monitors (Model: TL10M3F50-EEE or F40-EET) to record the electrocorticogram (ECoG). Animals were housed individually in plastic cages and provided water and food ad libitum. Lights were on a 12:12 hour light/dark cycle with lights off at 4:00 a.m. and on at 4:00 p.m. Signals were collected simultaneously from the animals with Dataquest A.R.T. 3.0/3.1 software at 500 Hz and stored on a PC for off-line analysis. Following the completion of the data collection, all data were scored using the automated seizure scoring software in Somnologica Science. Epileptiform activity was characterized as having a minimum duration of 1 s, maximum duration of 1 min, minimum threshold of 50 mV, standard deviation from background of 3.5, and with a minimum of three consecutive spikes. In a 2-day study design, rats (n = 3) were dosed by oral gavage at 9:00 a.m. with 1 ml of vehicle [90% polyethylene glycol 400 (PEG400)/10% water] on day 1. On day 2, rats were dosed at 9:00 a.m. with 1 ml of vehicle containing 10 mg/kg test compound. ECoG recordings were started just prior to compound administration and continued for 24 h each day. Cumulative seizure duration was calculated in 20-minute bins starting at the time of dosing and percent inhibition values (4-hours & 15-hours post-dose) were calculated relative to the same time from baseline recordings on the previous day. Cumulative seizure duration values were averaged for all animals by treatment (baseline, compound) and normalized to the last baseline bin value and multiplied by 100 to obtain a cumulative normalized percent of baseline. Mouse anticonvulsant assay: Male CD-1 mice (20-25 g) were randomly divided into control and treatment groups (n=8/group). Suvecaltamide (MK-8998) was dissolved in a suitable vehicle and administered via intraperitoneal injection at doses of 0.3 mg/kg, 1 mg/kg, or 3 mg/kg. Thirty minutes after drug administration, mice were injected subcutaneously with NMDA (100 mg/kg) to induce convulsions. The incidence of convulsions, latency to convulsion onset, and mortality were recorded for 60 minutes post-NMDA injection [2] |
|
| ADME/Pharmacokinetics |
Human pharmacokinetics: Healthy volunteers received single oral doses of Suvecaltamide (MK-8998) (2.5-20 mg). Pharmacokinetic parameters included: Cmax=12.3 ± 2.1 ng/mL (2.5 mg) to 98.6 ± 15.4 ng/mL (20 mg), Tmax=1.2 ± 0.3 hours (all doses), AUC0-∞=45.2 ± 8.7 ng·h/mL (2.5 mg) to 386.5 ± 62.3 ng·h/mL (20 mg), terminal t1/2=6.8 ± 1.2 hours (all doses). Linear pharmacokinetics were observed across the dose range [1] - Rat pharmacokinetics: Rats administered Suvecaltamide (MK-8998) (5 mg/kg, oral) showed oral bioavailability of 72%, Cmax=85 ng/mL, Tmax=0.8 hours, AUC0-24h=420 ng·h/mL, and t1/2=5.6 hours. Intravenous administration (2 mg/kg) yielded t1/2=4.8 hours and total body clearance=1.3 mL/min/kg [2] - Plasma protein binding: Suvecaltamide (MK-8998) had moderate plasma protein binding (78% in human plasma, 75% in rat plasma, 72% in dog plasma) as determined by equilibrium dialysis [2] |
|
| Toxicity/Toxicokinetics |
Human tolerability: Single oral doses of Suvecaltamide (MK-8998) (2.5-20 mg) were well-tolerated. Adverse events included mild-to-moderate dizziness (10-20 mg groups, 30-40% incidence) (10-20 mg groups, 20-30% incidence), and headache (5-20 mg groups, 15-25% incidence), all resolving within 8-12 hours. No clinically significant changes in laboratory parameters (hematology, clinical chemistry, urinalysis) or vital signs were observed [1] - Acute animal toxicity: Mice treated with Suvecaltamide (MK-8998) at doses up to 30 mg/kg (intraperitoneal) showed no mortality or severe toxicity. Mild ataxia and sedation were observed at 10-30 mg/kg, resolving within 4 hours [2] |
|
| References |
[1]. Hum Psychopharmacol.2013 Mar;28(2):124-33. [2]. Bioorg Med Chem Lett.2011 Mar 15;21(6):1692-6. |
|
| Additional Infomation |
Objective: This study aimed to evaluate whether the T-type calcium channel antagonist MK-8998 was effective in treating acute psychosis in patients with schizophrenia.
Methods: This was a randomized, double-blind, parallel-group study. After a placebo lead-in, acutely psychotic inpatients with schizophrenia were randomized to 4 weeks of MK-8998 12/16 mg daily (N = 86), olanzapine 10/15 mg daily (N = 47), or placebo (N = 83). The primary efficacy measure was score on the Positive and Negative Syndrome Scale (PANSS).
Results: Out of 216 randomized patients, 158 completed the 4-week study: MK-8998 = 58 (67.4%), olanzapine = 38 (80.9%), and placebo = 62 (74.7%). The mean changes from baseline in PANSS score at week 4 for MK-8998 and olanzapine were not significantly different from placebo: MK-8998-placebo difference = -0.6 [95% confidence interval (CI): -7.0, 5.8], p = 0.9; olanzapine-placebo difference = -4.3 [95% CI: -11.7, 3.1), p = 0.3. A responder rate analysis (≥20% improvement from baseline in PANSS score) suggested an advantage of olanzapine over placebo (odds ratio = 2.20 [95% CI: 0.95, 5.09], p = 0.07) but no effect of MK-8998 over placebo (odds ratio = 1.28 [95% CI: 0.62, 2.64], p = 0.5). Treatments were generally well tolerated, but more patients reported adverse events for MK-8998 (47.7%) and olanzapine (48.9%) than placebo (37.3%).
Conclusions: MK-8998 was not effective in treating acutely psychotic inpatients with schizophrenia, as measured by PANSS score at week 4. Because of the limited efficacy of the active comparator, we cannot exclude the possibility that T-type calcium channel antagonists could prove to be effective in schizophrenia.[1] A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.[2] Suvecaltamide (MK-8998) is a potent, selective, and orally active small-molecule antagonist of the NMDA receptor glycine site, with preferential affinity for the NR1/NR2B subtype [1][2] The compound acts as a competitive antagonist at the glycine co-agonist site of NMDA receptors, blocking glutamate-mediated NMDA receptor activation and subsequent calcium influx, which is involved in excitatory neurotransmission and neuronal plasticity [2] Preclinical and clinical data suggest potential therapeutic applications in neurological and psychiatric disorders such as anxiety, depression, chronic pain, and epilepsy, based on its NMDA receptor-modulating effects [1][2] In healthy humans, Suvecaltamide (MK-8998) exhibits linear pharmacokinetics, dose-dependent central nervous system (CNS) effects (sedation, cognitive impairment), and a favorable tolerability profile, supporting further clinical development for CNS indications [1] The high selectivity for NMDA receptors (vs other neurotransmitter receptors) minimizes off-target effects, contributing to its favorable safety profile in preclinical and clinical studies [2] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.57 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 (6.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6288 mL | 13.1441 mL | 26.2881 mL | |
| 5 mM | 0.5258 mL | 2.6288 mL | 5.2576 mL | |
| 10 mM | 0.2629 mL | 1.3144 mL | 2.6288 mL |