Dehydroaripiprazole (OPC-14857) HCl is the bioactive metabolite of Aripiprazole. Aripiprazole is an antipsychotic drug that is metabolized by CYP3A4 and CYP2D6, primarily to form Dehydroaripiprazole HCl. Dehydroaripiprazole HCl has antipsychotic activity equivalent to Aripiprazole.

Physicochemical Properties

Molecular Formula	C23H26CL3N3O2
Molecular Weight	482.83
Exact Mass	445.132
CAS #	1008531-60-9
Related CAS #	Dehydroaripiprazole;129722-25-4;Dehydro Aripiprazole-d8 hydrochloride;1215383-78-0
PubChem CID	24948424
Appearance	Typically exists as solid at room temperature
LogP	5.231
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	7
Heavy Atom Count	31
Complexity	597
Defined Atom Stereocenter Count	0
SMILES	Cl.O=C1NC2=C(C=CC(OCCCCN3CCN(C4=C(Cl)C(Cl)=CC=C4)CC3)=C2)C=C1
InChi Key	CUQHINIXYQSLAI-UHFFFAOYSA-N
InChi Code	InChI=1S/C23H25Cl2N3O2.ClH/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18;/h3-9,16H,1-2,10-15H2,(H,26,29);1H
Chemical Name	7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-1H-quinolin-2-one;hydrochloride
Synonyms	Dehydro Aripiprazole Hydrochloride; 1008531-60-9; DEHYDROARIPIPRAZOLE, HYDROCHLORIDE; Dehydroaripiprazole (hydrochloride); 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-1H-quinolin-2-one;hydrochloride; DTXSID70648054; AKOS040755398; 7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-2(1H)-quinolinone Hydrochloride;
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	5-HT1A Receptor 4.2 nM (Ki)
ln Vitro	Aripiprazole, a novel antipsychotic drug, is metabolized by CYP3A4 and CYP2D6 forming mainly its active metabolite dehydroaripiprazole. In this study, aripiprazole and dehydroaripiprazole serum levels of psychiatric patients were measured and related to dose, comedication, and clinical effects including therapeutic and side effects. Patients were treated with mean doses of 20 +/- 8 mg/day of aripiprazole (median 15 mg, range 7.5-60 mg). Serum levels correlated significantly with the dose (r = 0.419; P < 0.01), with a mean value of aripiprazole of 214 +/- 140 ng/ml. Mean concentrations of the active metabolite dehydroaripiprazole amounted to 40% of the parent compound. Comedication with CYP3A4 and CYP2D6 inducers or inhibitors changed serum levels up to 51%. Improvement was best in patients with a serum level between 150 and 300 ng/ml. No or only mild side effects were detected in patients, with aripiprazole plasma concentrations between 110 and 249 ng/ml. A total of 32% of the patients who received no other antipsychotic drug besides aripiprazole reported side effects; tension being the most frequent one. Since serum levels of aripiprazole and dehydroaripiprazole were highly variable between individuals, and distinct ranges were associated with good therapeutic response and minimal side effects, it seems likely that therapeutic drug monitoring can be helpful to improve the antipsychotic drug therapy. [1]
ln Vivo	Aripiprazole is widely used to treat schizophrenia. Plasma levels of aripiprazole and its active metabolite dehydroaripiprazole and their clinical responses in patients were explored. Forty-five (male/female: 19/26) patients with schizophrenia were treated with aripiprazole after a washout period of at least 3 days. There was no concomitant psychotropic except benzodiazepines for insomnia. The Positive and Negative Syndrome Scale (PANSS) was used to measure the clinical response at baseline and at weeks 2, 4, and 6. Blood was drawn at week 6 to measure the plasma concentrations of aripiprazole and dehydroaripiprazole. Patients with a PANSS score that decreased by more than 20% were defined as responders after 6 weeks of treatment. There was no difference in baseline PANSS scores or the daily dosage used between responders (n = 28) and nonresponders (n = 17) (15.0 ± 5.9 vs 12.9 ± 6.9 mg, respectively; P = 0.203). The responders showed a trend toward a higher plasma concentration of aripiprazole than nonresponders (234.4 ± 156.7 vs 163.5 ± 77.2 ng/mL, respectively; P = 0.117) and a significantly higher plasma concentration of dehydroaripiprazole (101.6 ± 58.0 vs 66.0 ± 48.4, respectively; P = 0.023). Higher plasma concentrations of aripiprazole and its active metabolite dehydroaripiprazole were noted in responders than nonresponders. Compared with Western patients, Oriental patients had higher plasma concentrations of aripiprazole and dehydroaripiprazole at the same dose. We suggest that therapeutic drug monitoring of aripiprazole will help improve the response in clinical practice. [2]
Enzyme Assay	Sample preparation and analysis [3] Stock solutions of aripiprazole and Dehydroaripiprazole at 1 mg/ml in methanol were prepared as reference standards. 0.5 μg/ml of aripiprazole and Dehydroaripiprazole in plasma were used as controls. Extraction of aripiprazole and Dehydroaripiprazole from plasma was performed as follows. A sample mixture 0.5 ml plasma, 1.5 ml phosphate buffer (0.1 M; pH 6.0) and 10 μl I.S. (carteolol; 0.2 μg/ml) were prepared in a 5 ml glass tube. All the samples were loaded onto the previously conditioned, (i.e., washed with 1.0 ml methanol and 1.0 ml phosphate buffer), SPE columns (Varian Bond Elut-Certify™ 130 mg 3 ml) that were connected to a vacuum manifold system. After washing with deionized water, the columns were acidified with 1.0 ml acetic acid (0.01 M; pH 3.3) and dried for 2 min under vacuum. Methanol (1.0 ml) was added and the columns were dried under vacuum. Elution was carried out with 1.5 ml (×2) of a freshly prepared mixture of ethyl acetate:28–30% ammonium hydroxide (98:2). The eluates were collected and evaporated to dryness under a nitrogen stream. Each sample was derivatized with 50 μl of previously prepared derivatization mixture (70 °C; 30 min) and injected for GC–MS analysis. Calibration[3] Calibration solutions were prepared in triplicate by spiking drug-free human plasma samples with known amounts of aripiprazole and Dehydroaripiprazole reference standards. Standard concentrations, 15.6, 31.3, 125.0, 250.0 and 500.0 ng/ml for aripiprazole and 7.8, 15.6, 62.5, 125.0 and 250.0 ng/ml for Dehydroaripiprazole, were prepared for constructing a calibration curve for each compound. The concentration of the internal standard (I.S.; carteolol) was 200 ng/ml. Quantification was carried out by selected ion monitoring (SIM) mode with a selected ion m/z 306 for aripiprazole and an ion m/z 290 for Dehydroaripiprazole and m/z 235 for I.S. The calibration curve for linear regression analysis was constructed by plotting the peak-area ratios of the analyte reference standards and the I.S. versus the standard concentrations.
Animal Protocol	Aripiprazole is a novel antipsychotic drug for the treatment of schizophrenia and schizoaffective disorders. In this study, a new method using gas chromatography–mass spectrometry (GC–MS) was developed and validated for the detection of aripiprazole and its main metabolite, dehydroaripiprazole, in plasma. Blood samples from seven psychiatric patients treated with aripiprazole (10–20 mg/day) underwent a solid-phase extraction (SPE) and N-methyl-N-trimethylsilytrifluoroacetamide (MSTFA) derivatization. The characteristic ions of mass spectra for aripiprazole and dehydroaripiprazole were m/z 306, 292, 218 and 304, 290, 218, respectively. Extraction recoveries from this method were 75.4% (n = 5) for aripiprazole and 102.3% (n = 5) for dehydroaripiprazole. The calibration curves of aripiprazole and dehydroaripiprazole were linear from 16 to 500 ng/ml (r2 = 0.999) and 8 to 250 ng/ml (r2 = 0.999), respectively. The respective limits of quantification (LOQs) for aripiprazole and dehydroaripiprazole evaluated in 0.5 ml of serum were 14.4 ng/ml and 6.9 ng/ml. Intra-assay and interassay precision and accuracy were within acceptable ranges. In this study, we also found that the mean trough concentrations in plasma at steady-state were 128.9 μg/l for aripiprazole and 30.1 μg/l for dehydroaripiprazole. [3]
ADME/Pharmacokinetics	Metabolism / Metabolites Dehydro-aripiprazole is a known human metabolite of aripiprazole.
References	[1]. Serum levels of aripiprazole and dehydroaripiprazole,\nclinical response and side effects. World J Biol Psychiatry.\n2008;9(3):212-8. [2]. Aripiprazole and dehydroaripiprazole plasma concentrations\nand clinical responses in patients with schizophrenia. J Clin\nPsychopharmacol. 2011 Dec;31(6):758-62. [3]. Detection and quantification of aripiprazole and its metabolite,\ndehydroaripiprazole, by gas chromatography\u2013mass spectrometry in blood\nsamples of psychiatric patients. JJournal of Chromatography B Volume 856, Issues 1–2, 1 September 2007, Pages 57-61.
Additional Infomation	The validated GC–MS method developed in this study provides a simple, accurate and reliable assay for the analysis of aripiprazole and dehydroaripiprazole in blood samples of psychiatric patients. The application of the SPE column, together with MSTFA-TMSI derivatization, generally produced better recovery and detection ability of the analytes than the liquid–liquid extraction (LLE) procedure. The detection limits of the analytes were far below the trough concentrations at steady-state indicating that this method is more than sufficient to detect aripiprazole and hydroxyaripiprazole in blood sample of the patients on commonly recommended doses. We suggest that GC–MS is the analytical instrument of choice for pharmacokinetic studies of aripiprazole in human blood sample. [3]

Solubility Data

Solubility (In Vitro)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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	2.0711 mL	10.3556 mL	20.7112 mL
	5 mM	0.4142 mL	2.0711 mL	4.1422 mL
	10 mM	0.2071 mL	1.0356 mL	2.0711 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.