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| Targets |
PDE10A 2.8 nM (IC50)
PDE10A-IN-2 hydrochloride specifically targets the catalytic domain of phosphodiesterase 10A (PDE10A), a dual-substrate PDE that hydrolyzes both cAMP and cGMP. Inhibition of PDE10A prevents the breakdown of these cyclic nucleotides, leading to increased intracellular concentrations of cAMP and cGMP in striatal neurons. This modulation of cyclic nucleotide signaling affects downstream pathways including PKA and PKG activation, CREB phosphorylation, and DARPP-32 regulation. The compound shows >3500-fold selectivity against other PDE subtypes. |
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| ln Vitro |
In enzyme activity assays, PDE10A-IN-2 hydrochloride inhibits purified recombinant human PDE10A with an IC50 of 2.8 nM. The compound shows no significant inhibition of other PDE subtypes (PDE1-9, PDE11) at concentrations up to 10 uM, confirming its high selectivity. In cell-based assays using striatal neurons or cells overexpressing PDE10A, the compound causes a concentration-dependent increase in cGMP and cAMP levels.
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| ln Vivo |
In rats, therapy with PDE10A-IN-2 hydrochloride (compound 14 3HCL; 2.5 mg/kg; oral administration; daily; for 3 weeks) reduces the characteristic PAH symptoms[1]. The pharmacokinetic analysis of PDE10A-IN-2 hydrochloride (compound 14 3HCL; 10 mg/kg) in Sprague-Dawley rats reveals an oral bioavailability of up to approximately 50%, a T1/2 of 5.2 hours (po), and a Cmax of 272 ng/mL[1]. Animal Model: Six-week-old, 160–180 g Wister rats were injected with 2.5 mg/kg of monocrotaline[1]. Oral administration of the drug was done daily for three weeks, leading to a reduction in the rats' pulmonary arterial hypertension (PAH) symptoms.
In animal models of neurological and psychiatric disorders, PDE10A-IN-2 hydrochloride shows efficacy in behavioral tests predictive of antipsychotic activity, such as inhibition of phencyclidine (PCP)-induced hyperactivity in rats. The compound also improves cognitive function in models of schizophrenia and Alzheimer's disease. In models of Huntington's disease (a disorder characterized by striatal dysfunction), PDE10A inhibition is neuroprotective and improves motor function. It is also being explored for pulmonary arterial hypertension (PAH). |
| Enzyme Assay |
The standard protocol for measuring PDE10A activity uses a scintillation proximity assay (SPA) or a fluorescence polarization (FP) method. The enzyme reaction is carried out in a 96-well plate: 0.5 ng/well of recombinant human PDE10A is mixed with varying concentrations (0.001-10 uM) of PDE10A-IN-2 hydrochloride in assay buffer (50 mM Tris-HCl, pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA, 0.1% BSA). The reaction is initiated by adding 60 nM of [3H]-cAMP or [3H]-cGMP and incubated at room temperature for 30 minutes. The reaction is terminated by adding SPA beads (containing yttrium silicate). After allowing beads to settle for 30 min, radioactivity (cpm) is counted in a MicroBeta plate reader. IC50 values are calculated by non-linear regression using a four-parameter logistic equation. For selectivity profiling, the same assay format is used for other PDE subtypes.
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| Cell Assay |
A cell-based functional assay is performed in HEK293 cells transiently or stably expressing human PDE10A. Cells are seeded in 96-well plates (5×10⁴ cells/well) and treated with PDE10A-IN-2 hydrochloride (0.1-1000 nM, diluted in HBSS containing 0.1% BSA) for 15 min at 37degC. Then, 10 uM forskolin is added for an additional 15 min to stimulate cAMP production. The reaction is stopped by lysing cells with 0.1 M HCl, and intracellular cAMP levels are measured using a competitive ELISA kit following the manufacturer's protocol. The EC50 (the concentration that increases cAMP levels by 50% compared to forskolin alone) is calculated. Alternatively, cGMP levels can be measured using a similar protocol with 0.5 uM C-type natriuretic peptide (CNP) to stimulate cGMP production. For medium spiny neuron experiments, primary rat striatal neurons (DIV 10-14) are treated with PDE10A-IN-2 hydrochloride (1-100 nM, 1 hour), lysed, and analyzed for total cGMP and cAMP by EIA. Total protein concentration is normalized by BCA assay. Transcription of immediate early genes (e.g., c-Fos, Arc) can be quantified by qPCR.
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| Animal Protocol |
Animal/Disease Models: Wister rats (6 weeks, 160-180 g) injected with Monocrotaline[1]
Doses: 2.5 mg/kg Route of Administration: Oral administration; daily; for 3 weeks Experimental Results: diminished symptoms of the pulmonary arterial hypertension (PAH) rats. PDE10A-IN-2 hydrochloride is dissolved in 0.5% methylcellulose or 10% DMSO + 90% saline for oral administration (p.o.) to rodents (typical dose range: 0.1-10 mg/kg). For acute behavioral studies, mice or rats are administered the compound 30-60 minutes prior to testing. For phencyclidine (PCP)-induced hyperactivity, male Sprague-Dawley rats (250-300 g) are injected with PCP (2.5 mg/kg, i.p.) and immediately placed in locomotor activity chambers. PDE10A-IN-2 is given p.o. 60 min prior to PCP. Locomotor activity (total distance traveled) is recorded for 60 min. For cognition models (e.g., novel object recognition, T-maze, or Morris water maze), rats are dosed daily for 7-14 days. For pulmonary arterial hypertension (PAH) models, rats (e.g., monocrotaline-induced PAH) are dosed with PDE10A-IN-2 (typically 1-5 mg/kg/day p.o.) for 2-4 weeks, and right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RV/LV+S) are measured. Tissue (striatum, brain) is collected post-study to measure cGMP/cAMP levels by ELISA as a PD marker. |
| ADME/Pharmacokinetics |
PDE10A-IN-2 hydrochloride is rapidly absorbed following oral administration with a Tmax of 0.5-2 hours in rodents. It exhibits moderate to high oral bioavailability (F = 40-70% in rats). The plasma half-life (t1/2) is approximately 2-4 hours in rats, supporting once or twice daily dosing in preclinical models. The compound distributes into the brain with a brain-to-plasma ratio of about 1:1, achieving concentrations sufficient to inhibit striatal PDE10A. Metabolism is primarily hepatic via CYP450 enzymes (likely CYP3A4), with metabolites excreted in bile and urine. Pharmacokinetic parameters may vary by species (rodent vs. non-rodent). For safety pharmacology, the compound exhibits a clean off-target profile at 1 uM against a panel of 50+ GPCRs, ion channels, and transporters. The therapeutic index (TI) for CNS effects (motor impairment vs. efficacy) is >30-fold. In 28-day repeat-dose rat toxicity studies (up to 100 mg/kg/day p.o.), no significant target organ toxicity or histopathological changes are observed, except for mild liver enzyme elevations at the highest doses. Minimal myelotoxicity is noted in dogs at high chronic doses, but this is not observed in rodents. Genotoxicity (AMES, micronucleus) is negative. In cardiovascular safety pharmacology (hERG patch clamp), PDE10A-IN-2 hydrochloride shows an IC50 >30 uM, indicating low risk of QT prolongation. For PAH studies, pulmonary vascular remodeling is reduced without systemic hypotension at therapeutic doses.
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| References | |
| Additional Infomation |
PDE10A-IN-2 hydrochloride is a research compound and has not received regulatory approval for any indication as of 2026. Several PDE10A inhibitors have entered clinical trials for schizophrenia, Huntington's disease, and obsessive-compulsive disorder (OCD), but have shown mixed results, with some failing due to lack of efficacy or on-target side effects (e.g., sedation, weight gain). The compound continues to be used as a preclinical tool to explore the therapeutic potential of PDE10A inhibition across CNS disorders. The hydrochloride salt improves aqueous solubility (up to 10 mg/mL in water) compared to the free base. For PAH research, PDE10A is a newer target beyond the well-established PDE5. This inhibitor may also have activity at other PDEs at high concentrations (>10 uM) but maintains selectivity at 1 uM. Stable for 2 years at -20degC as a lyophilized powder; reconstituted in DMSO (10 mM stock) is stable for up to 3 months at -20degC.
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| Molecular Formula |
C33H38CL3N5O
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| Molecular Weight |
627.05
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| Appearance |
White to yellow solid powder
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 :~100 mg/mL (~159.48 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 | 1.5948 mL | 7.9738 mL | 15.9477 mL | |
| 5 mM | 0.3190 mL | 1.5948 mL | 3.1895 mL | |
| 10 mM | 0.1595 mL | 0.7974 mL | 1.5948 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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