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Purity: ≥98%
Balipodect (formerly also known as TAK-063) is a novel, highly potent, orally bioavailable and selective phosphodiesterase 10A (PDE10A) inhibitor with potential usefulness in the treatment of schizophrenia. It inhibits PDE10A with an IC50 of 0.30 nM. TAK-063 has also excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of TAK-063 to mice elevated striatal 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg.
| Targets |
Phosphodiesterase 10A (PDE10A) (IC50 = 0.37 nM for human PDE10A; Ki = 0.15 nM for human PDE10A) [1]
Phosphodiesterase 10A (PDE10A) (IC50 = 0.42 nM for rat PDE10A; IC50 = 0.39 nM for mouse PDE10A) [2] |
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| ln Vitro |
In vitro activity: TAK-063 has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of TAK-063 to mice elevated striatal 3,5-cyclic adenosine monophosphate (cAMP) and 3,5-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg. TAK-063 at 0.3 and 1 mg/kg, p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP-dependent and cGMP-dependent protein kinases. TAK-063 at 0.3 and 1 mg/kg, p.o., strongly suppressed MK-801-induced hyperlocomotion that is often used as a predictive model for antipsychotic-like activity in rodents. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg, p.o. TAK-063 at 3 mg/kg, p.o., elicited a weak cataleptic response compared with haloperidol and olanzapine. Kinase Assay: Balipodect (TAK-063) is a highly potent, selective and orally active PDE10A inhibitor with IC50 of 0.30 nM; >15000-fold selectivity over other PDEs. TAK-063 (Balipodect) potently inhibited human recombinant PDE10A activity with an IC50 of 0.37 nM and Ki of 0.15 nM, showing >10,000-fold selectivity over other PDE isoforms (PDE1-9, PDE11) [1] In HEK293 cells stably expressing human PDE10A, TAK-063 (Balipodect) (0.1-100 nM) dose-dependently increased intracellular cAMP levels (EC50 = 1.2 nM) and cGMP levels (EC50 = 0.8 nM) by inhibiting PDE10A-mediated hydrolysis [1] In rat striatal slices, TAK-063 (Balipodect) (0.1-10 μM) increased cAMP and cGMP concentrations by 2.3-4.1-fold and 1.8-3.5-fold, respectively, with maximal effects at 10 μM [2] No significant inhibition of other PDE isoforms (PDE1A, PDE2A, PDE3B, PDE4B, PDE5A, PDE6C, PDE7A, PDE8A, PDE9A, PDE11A) was observed at concentrations up to 10 μM [1][2] |
| ln Vivo |
Balipodect (TAK-063) exhibits favorable pharmacokinetics, including high brain penetration in mice, and excellent selectivity (>15000-fold selectivity over other PDEs). When mice were given Balipodect (TAK-063) orally, their striatal levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) increased to 0.3 mg/kg. Additionally, at a minimum effective dose (MED) of 0.3 mg/kg, there was a significant suppression of phencyclidine (PCP)-induced hyperlocomotion[1]. At 0.3 and 1 mg/kg, po, balipodect (TAK-063) raised the levels of cAMP and cGMP in the rodent striatum and elevated the phosphorylation of important substrates of cAMP-dependent and cGMP-dependent protein kinases. At 0.3 and 1 mg/kg, po, balipodect (TAK-063) significantly reduced the hyperlocomotion induced by MK-801, which is frequently utilized as a model to predict antipsychotic-like activity in rodents. When combined with haloperidol and olanzapine, balipodect (TAK-063) at 3 mg/kg, po, elicited a weak cataleptic response[2]. At doses up to 3 mg/kg, po, balipodect (TAK-063) did not affect plasma prolactin or glucose levels.
In mice, oral administration of TAK-063 (Balipodect) (0.1-3 mg/kg) dose-dependently reduced amphetamine-induced hyperlocomotion (a model of psychosis) by 30-75%, with an ED50 of 0.5 mg/kg [2] In rats, TAK-063 (Balipodect) (0.3-3 mg/kg oral) inhibited phencyclidine (PCP)-induced deficits in prepulse inhibition (PPI) of startle response (a measure of sensory gating, impaired in schizophrenia) by 40-65% [2] In the rat conditioned avoidance response (CAR) model (predictive of antipsychotic efficacy), TAK-063 (Balipodect) (1-10 mg/kg oral) dose-dependently reduced avoidance responses by 35-80%, with an ED50 of 2.8 mg/kg [2] Single oral doses of TAK-063 (Balipodect) (1-10 mg/kg) in rats increased striatal cAMP and cGMP levels by 1.5-2.8-fold and 1.4-2.5-fold, respectively, at 1 hour post-dosing [2] In mice, TAK-063 (Balipodect) (0.3-3 mg/kg oral) increased dopamine and serotonin turnover in the striatum, as indicated by elevated levels of their metabolites (DOPAC, HVA, 5-HIAA) [2] |
| Enzyme Assay |
Human recombinant PDE10A was mixed with reaction buffer containing cAMP/cGMP (substrates) and MgCl2. TAK-063 (Balipodect) was serially diluted (0.01 nM-1 μM) and added to the mixture, which was incubated at 30°C for 60 minutes. The reaction was terminated by heating at 95°C for 5 minutes, and remaining cAMP/cGMP was quantified using a competitive immunoassay kit. IC50 values were calculated from concentration-response inhibition curves [1]
For Ki determination, PDE10A enzyme assays were performed with varying concentrations of cAMP (0.1-10 μM) and fixed concentrations of TAK-063 (Balipodect). The reaction mixture was incubated at 30°C for 45 minutes, and hydrolyzed substrates were measured by HPLC. Ki values were derived using Lineweaver-Burk plots to confirm competitive inhibition [1] Rat/mouse recombinant PDE10A enzyme assays were conducted similarly to human PDE10A assays, with reaction conditions optimized for rodent enzymes. TAK-063 (Balipodect) was tested at concentrations of 0.01 nM-1 μM, and IC50 values were calculated based on residual enzyme activity [2] |
| Cell Assay |
HEK293 cells stably expressing human PDE10A were seeded into 96-well plates and allowed to adhere overnight. Cells were preincubated with TAK-063 (Balipodect) (0.1 nM-100 nM) for 30 minutes, then stimulated with forskolin (to increase cAMP) or sodium nitroprusside (to increase cGMP) for 1 hour at 37°C. Cells were lysed, and intracellular cAMP/cGMP levels were quantified using specific ELISA kits. EC50 values for cAMP/cGMP elevation were determined [1]
Rat striatal slices (300 μm) were prepared and incubated in oxygenated Krebs-Ringer buffer at 37°C for 1 hour. TAK-063 (Balipodect) (0.1-10 μM) was added to the buffer, and slices were incubated for another 2 hours. Slices were homogenized, and cAMP/cGMP concentrations were measured by HPLC with electrochemical detection [2] |
| Animal Protocol |
Formulated in 0.5% (w/v) methylcellulose in distilled water; 0.3 mg/kg; p.o.
ICR mice Male ICR mice (20-25 g) were used for amphetamine-induced hyperlocomotion. Mice were randomized into groups (n=8 per group) and administered TAK-063 (Balipodect) (0.1, 0.3, 1, 3 mg/kg) or vehicle (0.5% methylcellulose + 0.1% Tween 80) by oral gavage 60 minutes before amphetamine (5 mg/kg intraperitoneal) injection. Locomotor activity was measured for 2 hours in an open-field apparatus using automated activity monitors [2] Male Sprague-Dawley rats (250-300 g) were used for PPI and CAR studies. For PPI: Rats were treated with TAK-063 (Balipodect) (0.3, 1, 3 mg/kg oral) or vehicle 60 minutes before PCP (5 mg/kg intraperitoneal) administration. PPI of startle response was measured using a startle reflex system 30 minutes after PCP injection [2] For CAR: Rats were trained to avoid an electric foot shock by moving to a safe compartment after a conditioned stimulus. Once trained, rats were treated with TAK-063 (Balipodect) (1, 3, 10 mg/kg oral) or vehicle 60 minutes before testing, and avoidance responses were recorded [2] For neurochemical studies, rats were administered TAK-063 (Balipodect) (1, 3, 10 mg/kg oral) or vehicle, euthanized at 1, 4, or 8 hours post-dosing, and striata were dissected. Tissue homogenates were analyzed for cAMP/cGMP, dopamine, serotonin, and their metabolites by HPLC [2] |
| ADME/Pharmacokinetics |
The oral bioavailability of TAK-063 (Balipodectt) was 78% in rats and 85% in dogs[1]. The plasma elimination half-life (t1/2) was 2.1 hours in rats, 4.3 hours in dogs, and 6.8 hours in cynomolgus monkeys[1]. In rats, peak plasma concentration (Cmax) was reached 1 hour after oral administration, exhibiting dose-proportional pharmacokinetic characteristics in the dose range of 0.3-10 mg/kg[2]. The drug has a large volume of distribution (Vd = 2.8 L/kg in rats), indicating its extensive tissue penetration[1]. Metabolic studies in human liver microsomes showed that TAK-063 (Balipodectt) is mainly metabolized by CYP3A4, with a smaller contribution from CYP2C9[1]. In rats, approximately 65% of the administered dose was excreted in feces (10%) and approximately 28% in urine, of which approximately 15% was excreted unchanged in feces [1]. The brain-to-plasma concentration ratio was 3.2 one hour after oral administration in rats [2].
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| Toxicity/Toxicokinetics |
In acute toxicity studies, single oral administration of TAK-063 (Balipodectt) up to 1000 mg/kg in rats and mice did not cause death or significant clinical toxicity [1]. In a 28-day repeated-dose toxicity study in rats, daily oral administration of doses up to 100 mg/kg did not cause changes in body weight, food consumption, or clinical chemical parameters (ALT, AST, creatinine, BUN) [1]. TAK-063 (Balipodectt) has a plasma protein binding rate of 92-94% in human plasma [1]. In human liver microsomes, no significant inhibition of CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) was observed at concentrations up to 10 μM [1].
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| References |
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| Additional Infomation |
Balipodect is being investigated in the clinical trial NCT01892189 (Effects of TAK-063 in preventing ketamine-induced changes in brain activity and psychotic-like symptoms in healthy adult men).
TAK-063 (Balipodect) is a potent, selective, orally effective phosphodiesterase 10A (PDE10A) inhibitor [1][2]. PDE10A is primarily expressed in the striatum and regulates the levels of cyclic nucleotides (cAMP, cGMP), which are involved in dopamine and glutamate signaling pathways, which are associated with schizophrenia [1][2]. This drug exerts an antipsychotic-like effect by inhibiting PDE10A, thereby increasing striatal cAMP and cGMP levels, regulating dopamine D1/D2 receptor signaling, and improving sensory gating and cognitive deficits[2]. It was originally developed for the treatment of schizophrenia, with the aim of improving positive symptoms (hallucinations, delusions) and negative symptoms (social withdrawal, anhedonia)[1][2]. Its high selectivity for PDE10A minimizes the off-target effects associated with non-selective PDE inhibitors[1]. |
| Molecular Formula |
C23H17FN6O2
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| Molecular Weight |
428.42
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| Exact Mass |
428.139
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| CAS # |
1238697-26-1
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| Related CAS # |
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| PubChem CID |
46848915
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
612.3±65.0 °C at 760 mmHg
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| Flash Point |
324.1±34.3 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.686
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| LogP |
2.35
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
755
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
KVHRYLNQDWXAGI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H17FN6O2/c1-32-21-15-29(19-9-8-17(14-18(19)24)28-13-5-11-25-28)27-22(23(21)31)20-10-12-26-30(20)16-6-3-2-4-7-16/h2-15H,1H3
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| Chemical Name |
1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.84 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 25.0 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: ≥ 2.5 mg/mL (5.84 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 25.0 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 | 2.3342 mL | 11.6708 mL | 23.3416 mL | |
| 5 mM | 0.4668 mL | 2.3342 mL | 4.6683 mL | |
| 10 mM | 0.2334 mL | 1.1671 mL | 2.3342 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.
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