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| Targets |
Kv7.2/7.3 and Kv7.3/7.5 potassium channels[1][2]
ICA-105665 activates neuronal Kv7.2/Kv7.3 (KCNQ2/3) and Kv7.3/Kv7.5 (KCNQ3/5) potassium channels, which are important regulators of neuronal excitability. By opening these channels, ICA-105665 hyperpolarizes neurons, reducing hyperexcitability. It also inhibits liver mitochondrial function and bile salt export protein (BSEP) transport (IC50 = 311 uM), but this occurs at concentrations much higher than those required for Kv7 channel activation. |
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| ln Vitro |
According to results from three assessments in two different human hepatocyte lots (LBN and HU4165), ICA-105665 (PF-04895162) does not exhibit potent cytotoxic properties in THLE and HepG2 cell lines (IC50 ~192 μM and 130 μM after 72 hours, respectively) or in human hepatocytes (AC50 for cell loss at 48 hours was >125 μM). Human hepatocytes treated with ICA-105665 (PF-04895162) at doses >11 μM for 25 minutes[1] have impaired mitochondrial respiratory reserve.
In vitro, ICA-105665 is a potent opener of neuronal Kv7.2/7.3 and Kv7.3/7.5 potassium channels. It has low cytotoxic potential in human hepatocytes but inhibits liver mitochondrial function and BSEP transport at an IC50 of 311 uM. The compound is CNS-penetrant and has antiepileptic effects. It has demonstrated broad-spectrum antiseizure activity in multiple in vitro seizure models. |
| ln Vivo |
In a 7-day rat toxicology investigation, dose-dependent increases of alanine aminotransferase (ALT), which may be suggestive of liver injury, were noted for ICA-105665 (PF-04895162). However, ALT elevations were not verified in a follow-up 7-day investigation, and no histological evidence of liver impairment was found. Additionally, transaminase increases and liver toxicity were not observed in 28-day or 6-month toxicity trials conducted in rats, and toxicity investigations lasting up to nine months in cynomolgus monkeys were similarly negative[2]. In several animal models, such as maximal electroshock, 6 Hz seizures, pentylenetetrazole, and electrical kindling, ICA-105665 (PF-04895162) has shown broad spectrum antiseizure efficacy at dosages ranging from <1 to 5 mg/kg[3].
In vivo, ICA-105665 has demonstrated broad-spectrum antiseizure activity in multiple animal models including maximal electroshock (MES), 6 Hz seizures (32 mA and 44 mA), pentylenetetrazole (PTZ)-induced seizures, and electrical kindling at doses ranging from <1 to 5 mg/kg. It penetrates the CNS and exhibits antiepileptic effects. The compound is orally active, and its antiepileptic efficacy has been established in rodent models. |
| Enzyme Assay |
For in vitro Kv7 channel activation assays, HEK293 cells co-expressing Kv7.2 and Kv7.3 (or Kv7.3 and Kv7.5) subunits are used in whole-cell patch-clamp recordings. Cells are held at -80 mV, and potassium currents are elicited by voltage-step protocols (e.g., from -120 mV to +60 mV). ICA-105665 is applied at increasing concentrations (0.1 nM to 100 uM). The EC50 for current enhancement is calculated. For selectivity, similar assays are performed on cells expressing other potassium or ion channels. Cell viability in hepatocytes is assessed by MTT or ATP-based assays.
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| Cell Assay |
For cell-based assays, primary rat cortical neurons or SH-SY5Y cells are treated with ICA-105665 at concentrations of 0.01-10 uM for 1-24 hours. Membrane potential can be measured using voltage-sensitive dyes (e.g., DiBAC4(3)). Neuronal firing rate can be assessed by multi-electrode array (MEA) recordings. Cytotoxicity is assessed by LDH release or MTT assay. For hepatotoxicity assessment, primary human hepatocytes are treated with ICA-105665 (0.1-1000 uM), and mitochondrial function is assessed by measuring oxygen consumption rate (Seahorse). BSEP transport inhibition is measured in membrane vesicles containing human BSEP.
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| Animal Protocol |
For in vivo efficacy studies, ICA-105665 is formulated in an appropriate oral vehicle (e.g., 0.5% methylcellulose or 5% DMSO in saline) and administered orally by gavage to rats or mice at doses ranging from 0.5-10 mg/kg. In maximal electroshock (MES) seizure models, seizures are induced by corneal or ear-clip electrodes, and protection from tonic hindlimb extension is assessed. In 6 Hz seizure models, seizures are induced by 6 Hz, 32 mA or 44 mA corneal stimulation for 3 seconds. The reduction in seizure duration or complete protection is measured. Efficacy is typically assessed 0.5-4 hours post-dose.
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| ADME/Pharmacokinetics |
ICA-105665 is orally active and penetrates the CNS. Detailed pharmacokinetic parameters are available in primary literature. In preclinical species (rats and dogs), ICA-105665 shows good oral bioavailability and a half-life suitable for once- or twice-daily dosing. The compound demonstrates brain-to-plasma ratios indicating efficient CNS penetration. For specific PK parameters (Cmax, Tmax, t1/2, AUC, oral bioavailability), researchers should consult the published literature, including the article by Bialer et al. ICA-105665 has low cytotoxic potential in human hepatocytes, but inhibits mitochondrial function at concentrations >300 uM.
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| Toxicity/Toxicokinetics |
ICA-105665 has low cytotoxic potential in human hepatocytes but inhibits liver mitochondrial function and BSEP transport at high concentrations (IC50 = 311 uM). This BSEP inhibition could potentially lead to drug-induced liver injury (DILI) at high doses or with chronic use. In animal seizure models at effective doses (<5 mg/kg), no significant toxicity has been reported. Comprehensive toxicology studies have likely been conducted to support preclinical development. Researchers should consult primary literature for detailed safety data.
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| References |
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| Additional Infomation |
ICA-105665 is a novel small molecule compound for the treatment of epilepsy. It is a novel KCNQ ion channel opener, and preclinical studies have shown it to have broad activity in various epilepsy models. Furthermore, ICA-105665 has also shown activity in certain neuropathic pain models.
Drug Indications Its applications are under investigation for the treatment of epilepsy.Mechanism of Action ICA-105665 activates KCNQ ion channel subtypes, which are ideal targets for the treatment of epilepsy due to their function and genetic association with epileptic seizures. ICA-105665 (PF-04895162) is a research compound that has been studied in preclinical models of epilepsy. It is not approved for clinical use. The compound represents a Kv7 channel opener approach to seizure control, distinct from benzodiazepines (GABA-A modulators) or sodium channel blockers. It may have advantages over the related compound retigabine (ezogabine), which was approved for epilepsy but discontinued due to skin and retinal pigmentation issues. ICA-105665 is a valuable research tool for studying Kv7 channel function in epilepsy. It should be stored at -20degC, protected from moisture and light. |
| Molecular Formula |
C19H15F2N3O2
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|---|---|
| Molecular Weight |
355.338111162186
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| Exact Mass |
355.113
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| CAS # |
2694728-63-5
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| PubChem CID |
70838704
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| Appearance |
White to off-white solid powder
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| LogP |
2.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
26
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| Complexity |
600
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CC1C2=NC3=C(C=CC(=C3)F)C(=O)N2NC(=O)CC4=CC=C(C=C4)F
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| InChi Key |
QVQACHQOSXTOLH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H15F2N3O2/c20-13-5-1-11(2-6-13)9-17(25)23-24-18(12-3-4-12)22-16-10-14(21)7-8-15(16)19(24)26/h1-2,5-8,10,12H,3-4,9H2,(H,23,25)
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| Chemical Name |
N-(2-cyclopropyl-7-fluoro-4-oxoquinazolin-3-yl)-2-(4-fluorophenyl)acetamide
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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: 250 mg/mL (703.55 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8142 mL | 14.0710 mL | 28.1421 mL | |
| 5 mM | 0.5628 mL | 2.8142 mL | 5.6284 mL | |
| 10 mM | 0.2814 mL | 1.4071 mL | 2.8142 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/NCT00979004
Conditions:EpilepsyLink: https://clinicaltrials.gov/ct2/show/NCT00962663
Conditions:HealthyProducts are for research use only; We do not sell to patients
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