ICA-105665 (PF-04895162) is a potent orally bioactive neuronal Kv7.2/7.3 and Kv7.3/7.5 potassium channel agonist. ICA-105665 inhibits hepatic mitochondrial function and bile salt export protein (BSEP) transport (IC50 of 311 μM). ICA-105665 penetrates the BBB (blood-brain barrier) and has anti-epileptic effects.

Physicochemical Properties

Molecular Formula	C19H15F2N3O2
Molecular Weight	355.338111162186
Exact Mass	355.113
CAS #	2694728-63-5
PubChem CID	70838704
Appearance	White to off-white solid powder
LogP	2.6
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	3
Heavy Atom Count	26
Complexity	600
Defined Atom Stereocenter Count	0
InChi Key	QVQACHQOSXTOLH-UHFFFAOYSA-N
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)
Chemical Name	N-(2-cyclopropyl-7-fluoro-4-oxoquinazolin-3-yl)-2-(4-fluorophenyl)acetamide
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	Kv7.2/7.3 and Kv7.3/7.5 potassium channels[1][2]
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.
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].
References	[1]. Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis. Pharmacol Res Perspect. 2019 Feb;7(1):e00467. [2]. Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity. Pharmacol Res Perspect. 2019 Oct 9;7(6):e00523. [3]. Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy. Epilepsia. 2013 Aug;54(8):1437-43. [4]. Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res. 2013 Jan;103(1):2-30.
Additional Infomation	ICA-105665 is a novel small molecule compound for the treatment of epilepsy. It is a novel opener of the KCNQ ion channel which in preclinical studies has demonstrated a broad spectrum of activity in models of epilepsy. In addition, ICA-105665 has also demonstrated activity in certain models of neuropathic pain. Drug Indication Investigated for use/treatment in epilepsy. Mechanism of Action ICA-105665 is an activator of subtypes of KCNQ ion channels, which are attractive targets for the treatment of epilepsy based on their function and genetic linkage to a seizure disorder.

Solubility Data

Solubility (In Vitro)

DMSO: 250 mg/mL (703.55 mM)

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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (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.