Rimtuzalcap (CAD-1883) is a first-in-class, selective PAM (positive allosteric modulator) of small conductance calcium-activated potassium channels (SK channels). Rimtuzalcap may be utilized in the research of movement disorders such as essential tremor (ET) and spinocerebellar ataxia (SCA).

Physicochemical Properties

Molecular Formula	C18H24F2N6O
Molecular Weight	378.419569969177
Exact Mass	378.197
CAS #	2167246-24-2
PubChem CID	132207249
Appearance	White to off-white solid powder
LogP	3.2
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	4
Heavy Atom Count	27
Complexity	483
Defined Atom Stereocenter Count	0
SMILES	FC1(CCC(CC1)NC1C=C(N=C(N2C=CC(C)=N2)N=1)N1CCOCC1)F
InChi Key	OVLIDRAJVMUEMC-UHFFFAOYSA-N
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)
Chemical Name	N-(4,4-difluorocyclohexyl)-2-(3-methylpyrazol-1-yl)-6-morpholin-4-ylpyrimidin-4-amine
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 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)

Biological Activity

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].
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].
References	[1]. Crystalline forms of potassium channel modulators. WO2020086456A1.
Additional Infomation	Rimtuzalcap is a novel modulator of small-conductance calcium-activated potassium channels that is under investigation for the treatment of essential tremor. Mechanism of Action Rimtuzalcap is a positive allosteric modulator of small-conductance calcium-activated K+ channels (SK channels). 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. 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. 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.

Solubility Data

Solubility (In Vitro)

DMSO: 250 mg/mL (660.64 mM)

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. 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. 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 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	2.6426 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.