This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.
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Identification
- Generic Name
- Rimtuzalcap
- DrugBank Accession Number
- DB16733
- Background
Rimtuzalcap is a novel modulator of small-conductance calcium-activated potassium channels that is under investigation for the treatment of essential tremor.3
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for Rimtuzalcap (DB16733)
- Weight
- Average: 378.428
Monoisotopic: 378.197965743 - Chemical Formula
- C18H24F2N6O
- Synonyms
- N-(4,4-difluorocyclohexyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-morpholinopyrimidin-4-amine
- Rimtuzalcap
- External IDs
- CAD-1883
- WHO 11140
Pharmacology
- Indication
Not Available
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Rimtuzalcap is thought to decrease the firing of neurons in the olivo-cerebellar network which are theorized to contribute to the dysfunction of oscillatory neuronal input to the motor cortex that results in the presentation of motor tremors in the typical 4-12 Hz band associated with essential tremor.1,3 Inhibition of this dysfunctional firing may provide benefit to patients with essential tremor.
- Mechanism of action
Rimtuzalcap is a positive allosteric modulator of small-conductance calcium-activated K+ channels (SK channels). 3 It is thought to exert its activity on essential tremor through increasing SK channel activity in the Purkinje cells of the cerebellar cortex resulting in hyperpolarization and consequently, a slower firing rate.2 These Purkinje cells have a glutamatergic excitatory input to deep cerebellar neurons in the dentate nucleus which themselves exert the same input on the ventral intermediate nucleus in the thalamocortical system.1 From there the ventral intermediate nucleus exerts excitatory input to the motor cortex, producing an effect on motor function. It is the decrease in the activity of this pathway through targeting Purkinje cell firing rate that is thought to have a beneficial impact on essential tremor.
Target Actions Organism ASmall conductance calcium-activated potassium channel protein 1 positive allosteric modulatorHumans ASmall conductance calcium-activated potassium channel protein 2 positive allosteric modulatorHumans USmall conductance calcium-activated potassium channel protein 3 positive allosteric modulatorHumans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Categories
- Drug Categories
- Not Available
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- USO2D5J77R
- CAS number
- 2167246-24-2
- InChI Key
- OVLIDRAJVMUEMC-UHFFFAOYSA-N
- InChI
- 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)
- IUPAC Name
- N-(4,4-difluorocyclohexyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-(morpholin-4-yl)pyrimidin-4-amine
- SMILES
- CC1=NN(C=C1)C1=NC(NC2CCC(F)(F)CC2)=CC(=N1)N1CCOCC1
References
- General References
- Zhang X, Santaniello S: Role of cerebellar GABAergic dysfunctions in the origins of essential tremor. Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13592-13601. doi: 10.1073/pnas.1817689116. Epub 2019 Jun 17. [Article]
- Hosy E, Piochon C, Teuling E, Rinaldo L, Hansel C: SK2 channel expression and function in cerebellar Purkinje cells. J Physiol. 2011 Jul 15;589(Pt 14):3433-40. doi: 10.1113/jphysiol.2011.205823. Epub 2011 Apr 26. [Article]
- Clinical Trial: NCT03688685 [Link]
- External Links
- ChemSpider
- 81367401
- ChEMBL
- CHEMBL4650330
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data2 Completed Treatment Essential Tremor 1 somestatus stop reason just information to hide 2 Withdrawn Treatment ARCA1 - Autosomal Recessive Cerebellar Ataxia Type 1 / Spinocerebellar Ataxia / Spinocerebellar Ataxia 3 / Spinocerebellar Ataxia Type 1 / Spinocerebellar Ataxia Type 10 / Spinocerebellar Ataxia Type 17 / Spinocerebellar Ataxia Type 6 / Spinocerebellar Ataxia Type 7 / Spinocerebellar Ataxia Type 8 / Spinocerebellar Ataxias Type 2 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.561 mg/mL ALOGPS logP 3.1 ALOGPS logP 2.78 Chemaxon logS -2.8 ALOGPS pKa (Strongest Basic) 3.72 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 68.1 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 101.56 m3·mol-1 Chemaxon Polarizability 39.18 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0009000000-b233714fd7067f3753c6 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-0009000000-b711be9bfecb641015f8 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0019000000-ea2d5f7f16e8ebcf89f6 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-1039000000-596477266372592e4951 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-03y0-0079000000-e1e0c05c6532e88a378f Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4r-1955000000-1aa347f5bd717b8caa3a Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Positive allosteric modulator
- General Function
- Small conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening (PubMed:17142458, PubMed:8781233, PubMed:9287325). The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of about 3 picosiemens (PubMed:8781233). Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV (Probable). Activation is followed by membrane hyperpolarization (By similarity). Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization (By similarity)
- Specific Function
- calcium-activated potassium channel activity
- Gene Name
- KCNN1
- Uniprot ID
- Q92952
- Uniprot Name
- Small conductance calcium-activated potassium channel protein 1
- Molecular Weight
- 59986.87 Da
References
- Clinical Trial: NCT03688685 [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Positive allosteric modulator
- General Function
- Small conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening (PubMed:10991935, PubMed:33242881, PubMed:9287325). The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of about 3 picosiemens (PubMed:10991935). Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV (PubMed:10991935). The inward rectification could be due to a blockade of the outward current by intracellular divalent cations such as calcium and magnesium and could also be due to an intrinsic property of the channel pore, independent of intracellular divalent ions. There are three positively charged amino acids in the S6 transmembrane domain, close to the pore, that collectively control the conductance and rectification through an electrostatic mechanism. Additionally, electrostatic contributions from these residues also play an important role in determining the intrinsic open probability of the channel in the absence of calcium, affecting the apparent calcium affinity for activation. Forms an heteromeric complex with calmodulin, which is constitutively associated in a calcium-independent manner. Channel opening is triggered when calcium binds the calmodulin resulting in a rotary movement leading to the formation of the dimeric complex to open the gate (By similarity). Plays a role in the repolarization phase of cardiac action potential (PubMed:13679367)
- Specific Function
- alpha-actinin binding
- Gene Name
- KCNN2
- Uniprot ID
- Q9H2S1
- Uniprot Name
- Small conductance calcium-activated potassium channel protein 2
- Molecular Weight
- 63759.03 Da
References
- Clinical Trial: NCT03688685 [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Positive allosteric modulator
- General Function
- Small conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening (PubMed:12808432, PubMed:20562108, PubMed:31155282, PubMed:36502918). The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of 10 picosiemens (PubMed:12808432, PubMed:20562108, PubMed:31155282, PubMed:36502918). Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV (PubMed:12808432). Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization (By similarity)
- Specific Function
- calmodulin binding
- Gene Name
- KCNN3
- Uniprot ID
- Q9UGI6
- Uniprot Name
- Small conductance calcium-activated potassium channel protein 3
- Molecular Weight
- 81384.63 Da
References
- Clinical Trial: NCT03688685 [Link]
Drug created at September 21, 2021 20:50 / Updated at June 02, 2023 02:07