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| Targets |
Rimtuzalcap selectively targets small-conductance calcium-activated potassium channels (SK channels), specifically the KCa2.2 (SK2) and KCa2.3 (SK3) subtypes. It acts as a positive allosteric modulator (PAM), enhancing SK channel activity without directly activating the channels. This mechanism is expected to reduce neuronal hyperexcitability, which underlies the pathophysiology of movement disorders such as essential tremor and spinocerebellar ataxia.
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| ln Vitro |
Compound 1, or rimtuzalcap, is a powerful small molecule that modulates potassium ion channels. It has been shown to have tremendous therapeutic potential in treating a range of disorders marked by potassium ion channel dysfunction as well as dysfunction resulting from other factors that affect these potassium channels[1].
In vitro, rimtuzalcap enhances SK channel activity through positive allosteric modulation. It reduces the firing rate of Purkinje cells in cerebellar slices by approximately 40%, consistent with the anticipated therapeutic mechanism of SK channel potentiation. Sequential bath application of 1 or 3 uM CAD-1883 results in a partial reversal of the increased coefficient of variation of the interspike interval seen in cerebellar slices from 11-month-old spinocerebellar ataxia-2 (SCA2) 580 mice. This suggests that rimtuzalcap normalizes Purkinje cell firing patterns. |
| ln Vivo |
Rimtuzalcap (CAD-1883) decreases Purkinje cell firing rate by around 40%, which is in line with the positive allosteric regulation of SK channels predicted as the therapeutic mechanism. Cerebellar slices from 11-month-old spinocerebellar ataxia-2 58Q mice show a partial reversal of the increased coefficient of variation of the interspike interval upon sequential bath administration of 1 or 3 µM CAD-1883[1].
In vivo, rimtuzalcap is expected to reduce motor symptoms in models of essential tremor and spinocerebellar ataxia by enhancing SK channel activity and reducing neuronal hyperexcitability. The compound decreases Purkinje cell firing rate by about 40% in ex vivo cerebellar slices, aligning with its expected therapeutic action. Rimtuzalcap has shown potential in preclinical models of movement disorders, and its safety and efficacy are being evaluated in clinical studies. |
| Enzyme Assay |
To assess SK channel modulation, CHO or HEK293 cells expressing recombinant human SK2 (KCa2.2) or SK3 (KCa2.3) channels are used in patch-clamp electrophysiology experiments. Cells are held at -80 mV, and SK channel currents are elicited by application of a calcium concentration clamp (e.g., 1 uM free Ca2+) or via co-expression of calmodulin and a calcium sensor. Rimtuzalcap is perfused at increasing concentrations (0.1-10 uM). The fold-increase in current amplitude is measured, and EC50 for positive modulation is calculated.
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| Cell Assay |
For cell-based assays, primary cerebellar slices from wild-type or SCA2 mouse models are used. Slices are bathed in artificial cerebrospinal fluid (aCSF) in a recording chamber. Purkinje cells are identified by morphology and location. Cell-attached or whole-cell patch-clamp recordings are performed. Rimtuzalcap (1-3 uM) is bath-applied, and changes in firing rate, coefficient of variation of interspike interval, and action potential waveform are analyzed. For viability, slices are assessed for tissue health by propidium iodide uptake or LDH release.
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| Animal Protocol |
For ex vivo studies, cerebellar slices are prepared from SCA2 (e.g., SCA2-580) or wild-type mice (age 11-12 months). Slices are incubated in oxygenated aCSF for at least 1 hour to recover. Slices are then transferred to a recording chamber and continuously perfused with aCSF at 32-34degC. Rimtuzalcap (1-3 uM) is bath-applied, and Purkinje cell firing rates are recorded by cell-attached patch-clamp. Recordings are typically stable for 30-60 minutes. For in vivo studies, rimtuzalcap is formulated in an oral vehicle.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for rimtuzalcap are limited in publicly available sources. The compound is described as a positive allosteric modulator, suggesting that it has suitable properties for oral administration and CNS penetration to reach SK channels in the cerebellum and other brain regions. For species-specific PK parameters (Cmax, Tmax, t1/2, oral bioavailability, brain-to-plasma ratio), researchers should consult the primary literature or conduct pilot studies in their model system.
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| Toxicity/Toxicokinetics |
Toxicology data for rimtuzalcap have been generated as part of preclinical development. In animal studies at therapeutic doses, no significant adverse events have been reported. The compound's mechanism as a positive allosteric modulator (rather than a direct agonist) may offer a favorable safety profile by avoiding over-activation of SK channels. Comprehensive toxicology reports are not publicly available; researchers should consult published safety data from clinical studies.
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| References | |
| Additional Infomation |
Rimtuzalcap is a novel low-conductivity calcium-activated potassium channel modulator currently under investigation for its efficacy in treating essential tremor. Mechanism of Action Rimtuzalcap is a positive allosteric modulator of low-conductivity calcium-activated potassium channels (SK channels). It is believed to exert its therapeutic effect on essential tremor by increasing the activity of SK channels in Purkinje cells of the cerebellar cortex, leading to hyperpolarization and thus reducing the firing rate. These Purkinje cells send glutamatergic excitatory inputs to cerebellar neurons deep in the dentate nucleus, which in turn send the same inputs to the ventral intermediate nucleus of the thalamic cortex. The ventral intermediate nucleus then sends excitatory inputs to the motor cortex, thereby affecting motor function. Targeting the firing rate of Purkinje cells to reduce the activity of this pathway is thought to have a beneficial effect on essential tremor.
Rimtuzalcap (CAD-1883) is a first-in-class investigational drug that has been studied in clinical trials for essential tremor (ET) and spinocerebellar ataxia (SCA). It has demonstrated positive modulatory effects on SK channels and reduced Purkinje cell hyperexcitability. The compound is not yet approved for clinical use. It is intended for research purposes and should be stored at 4degC, protected from light. Standard laboratory safety precautions should be taken when handling rimtuzalcap. |
| Molecular Formula |
C18H24F2N6O
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| Molecular Weight |
378.419569969177
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| Exact Mass |
378.197
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| CAS # |
2167246-24-2
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| PubChem CID |
132207249
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| Appearance |
White to off-white solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
483
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1(CCC(CC1)NC1C=C(N=C(N2C=CC(C)=N2)N=1)N1CCOCC1)F
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| InChi Key |
OVLIDRAJVMUEMC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H24F2N6O/c1-13-4-7-26(24-13)17-22-15(21-14-2-5-18(19,20)6-3-14)12-16(23-17)25-8-10-27-11-9-25/h4,7,12,14H,2-3,5-6,8-11H2,1H3,(H,21,22,23)
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| Chemical Name |
N-(4,4-difluorocyclohexyl)-2-(3-methylpyrazol-1-yl)-6-morpholin-4-ylpyrimidin-4-amine
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: 250 mg/mL (660.64 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.50 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 20.8 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: ≥ 2.08 mg/mL (5.50 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 20.8 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: ≥ 2.08 mg/mL (5.50 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 | 2.6426 mL | 13.2128 mL | 26.4257 mL | |
| 5 mM | 0.5285 mL | 2.6426 mL | 5.2851 mL | |
| 10 mM | 0.2643 mL | 1.3213 mL | 2.6426 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/NCT03688685
Conditions:Essential TremorLink: https://clinicaltrials.gov/ct2/show/NCT04301284
Conditions:Spinocerebellar Ataxias|Spinocerebellar Ataxia Type 1|Spinocerebellar Ataxia Type 2|Spinocerebellar Ataxia Type 3|Spinocerebellar Ataxia Type 6|Spinocerebellar Ataxia Type 7|Spinocerebellar Ataxia Type 8|Spinocerebellar Ataxia Type 10|Spinocerebellar Ataxia Type 17|ARCA1 - Autosomal Recessive Cerebellar Ataxia Type 1Products are for research use only; We do not sell to patients
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