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| 25mg |
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Purity: ≥98%
PF-06256142 is a novel, potent and selective orthosteric agonist of the D1 receptor with D1 EC50 of 30 nM and D1 binding Ki of 12 nM. In comparison to other catechol-containing agonists and dopamine, it has lessened receptor desensitization. For the better part of four decades, the search for D1 subtype-selective agonists possessing drug-like qualities has been an ongoing challenge. As catecholamines, all known D1-selective agonists cause receptor desensitization and have fast metabolisms, which limits their use as treatments for long-term conditions like schizophrenia and Parkinson's disease. Our high-throughput screening efforts on D1 yielded a single non-catecholamine hit PF-4211 (6) that was developed into a series of potent D1 receptor agonist leads with high oral bioavailability and CNS penetration. This series' locked biaryl ring system, which causes atropisomerism, is a crucial structural component.
| Targets |
Human D1 Receptor ( IC50 = 33 nM )
Dopamine D1 receptor (orthosteric agonist; D1 cAMP EC50: 33 nM, 91% emax; D1 binding Ki: 11.9 nM) Dopamine D5 receptor (Ki: 4.8 nM) Dopamine D2 receptor (Ki >10 µM) Muscarinic M1 receptor (antagonist, IC50: 4.9 µM) Cannabinoid CB1 receptor (antagonist, IC50: 2.1 µM) Histamine H1 receptor (antagonist, IC50: 4.6 µM) Nav 1.5 channel (antagonist, IC50: 1.1 µM) hERG channel (IC50: ~12 µM) [1] |
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| ln Vitro |
PF-06256142, an antagonist, demonstrates IC50 values less than 5 μM at the following 4 targets: H1 (4.6 μM), M1 (4.9 μM), CB1 (2.1 μM), and Nav 1.5 (1.1 μM) [1].
PF-06256142 exhibits an IC50 for hERG of roughly 12 μM [1]. PF-06256142 demonstrates a 4.8 nM Ki for D5, which is significantly more selective than D2 (Ki>10 μM)[1]. PF-06256142 is a potent and selective orthosteric agonist at the dopamine D1 receptor. In HEK293T cells overexpressing the human D1 receptor, it stimulated cAMP production with an EC50 of 33 nM and 91% maximal efficacy relative to dopamine. In a radioligand binding assay using [³H]SCH-23390, it displaced the ligand from the human D1 receptor with a Ki of 11.9 nM. It exhibited high selectivity over the D2 receptor (Ki >10 µM) but similar affinity for the D5 receptor (Ki 4.8 nM). In a broad pharmacology panel, it showed weak antagonist activity (>5 µM) at M1, CB1, H1 receptors and Nav1.5 channel, and had a hERG IC50 of approximately 12 µM. In cultured rat primary striatal neurons endogenously expressing D1 receptors, pretreatment with PF-06256142 (10 µM) induced significantly less receptor desensitization (~20%) compared to catecholamine agonists like dopamine (~60-100%) upon subsequent challenge with agonist SKF-81297. [1] |
| ln Vivo |
PF-06256142 shows a strong oral bioavailability (rat 85%) after oral dosing (5 mg/kg)[1].
PF-06256142 has a terminal elimination half-life (2.3 hours) in rats after being injected intravenously at a dose of 5.0 mg/kg[1]. Administration of its racemate (compound 29, 10 and 32 mg/kg, SC) to mice significantly increased locomotor activity during the 0-120 minute post-dose period compared to vehicle. This locomotor-stimulating effect was dose-dependently attenuated by pre-treatment with the D1 antagonist SCH-23390, confirming the D1-mediated mechanism of action in vivo. [1] |
| Enzyme Assay |
D1 Receptor cAMP Functional Assay: Activity was measured using a homogeneous time-resolved fluorescence (HTRF) kit. Assays were performed in HEK293 cell lines overexpressing the human D1 receptor. Compound serial dilutions were incubated with cells, and intracellular cAMP levels were detected using the HTRF kit according to the manufacturer's instructions. Data were analyzed using a cAMP standard curve to convert signals to nM cAMP, then normalized to the maximal response elicited by dopamine. [1]
Radioligand Binding Assay: Binding affinity for the human D1 receptor was determined by competition binding using the radiolabeled antagonist [³H]SCH-23390. Membranes from cells expressing the receptor were incubated with the radioligand and various concentrations of the test compound. Non-specific binding was defined in the presence of a high concentration of a competing ligand. After incubation and separation of bound from free radioligand, the amount of bound radioactivity was measured to determine Ki values. [1] |
| Cell Assay |
D1 Receptor Desensitization Assay in Primary Neurons: Cultured rat primary striatal neurons endogenously expressing D1 receptors were used. Cells were incubated with 10 µM of test agonists (including PF-06256142) for 90 minutes. Following extensive washing to remove the agonist, cells were challenged with the D1 catecholamine agonist SKF-81297 (compound 4) to measure the subsequent cAMP response. The degree of desensitization was calculated by comparing this response to that in vehicle-pretreated cells. [1]
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| Animal Protocol |
Rat
5.0 mg/kg for i.v.; 5 mg/kg for oral (Pharmacokinetic Analysis) Intravenous injection and oral administration Mouse Locomotor Activity Assay: The D1-mediated functional activity of compounds was assessed by measuring locomotor activity in habituated mice. The racemic compound 29 was administered subcutaneously (SC) at doses of 0.32, 1, 3.2, 10, and 32 mg/kg. Locomotor activity (total beam breaks) was recorded for 120 minutes post-dose. For antagonist blockade studies, mice were pretreated with the D1 antagonist SCH-23390 (compound 32) at various doses (0.001 to 0.032 mg/kg, SC) 30 minutes prior to administration of compound 29 (10 mg/kg, SC). [1] Rat Pharmacokinetics Study: For intravenous (IV) pharmacokinetics, PF-06256142 was dosed as a solution in saline containing 3 molar equivalents of HCl at 5.0 mg/kg via IV bolus. For oral (PO) pharmacokinetics and bioavailability, it was dosed at 5 mg/kg in a 0.5% methylcellulose vehicle. Brain exposure was assessed following a single subcutaneous dose of 5.6 mg/kg. Blood, plasma, and brain samples were collected at various time points for analysis. [1] |
| ADME/Pharmacokinetics |
PF-06256142 exhibits low intrinsic in vitro clearance in human liver microsomes (22 mL/min/kg). It possesses high passive permeability (RRCK: 31 x 10⁻⁶ cm/sec) and low efflux ratios of MDR1 (1.7) and BCRP (1.3) transporters. In rats, it exhibits low systemic clearance (23 mL/min/kg), a moderate half-life (2.3 h), and high oral bioavailability (85%). It demonstrates good brain permeability, with a free brain/plasma concentration ratio (Cb,u/Cp,u) of 0.8 and a total brain/plasma AUC ratio (B/P) of 2.2. It maintains high plasma protein binding rates across different species (human, rat, mouse Fu,p = 0.04; rat Fu,b = 0.02). The measured ElogD was 3.4 (cLogP was 4.0). [1]
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| Toxicity/Toxicokinetics |
High plasma protein binding rate (free fraction, Fu,p: 0.04 in humans, rats, and mice; Fu,b in rat brain tissue: 0.02).
In vitro experiments showed that this compound has weak antagonistic activity against hERG channels, with an IC50 value of approximately 12 µM. [1] |
| References | |
| Additional Infomation |
PF-06256142 is a blocked transisomer compound formed by a blocked biaryl bond with a high rotational barrier (>15 kcal/mol). The active enantiomer (31) was separated by chiral supercritical fluid chromatography (SFC). Its absolute stereochemical configuration was determined by X-ray crystallography and vibrational circular dichroism (VCD). It is a non-catecholamine D1 receptor agonist that reduces the tendency for D1 receptor desensitization and β-arrestin recruitment compared to conventional catecholamine agonists (such as dopamine), as demonstrated in primary neuron cultures. This pharmacological property of sustained signal transduction and reduced desensitization is considered potentially beneficial for the treatment of chronic neurological disorders such as Parkinson's disease and schizophrenia. [1]
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| Molecular Formula |
C21H16N4O2
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|---|---|
| Molecular Weight |
356.37734413147
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| Exact Mass |
356.13
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| Elemental Analysis |
C, 70.77; H, 4.53; N, 15.72; O, 8.98
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| CAS # |
1609583-14-3
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| Related CAS # |
(Rac)-PF-06256142; 1609580-97-3; (R)-PF-06256142; 1609583-15-4
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| PubChem CID |
75201901
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| Appearance |
Solid powder
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| LogP |
4.3
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
520
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HWAIAGZSWHOLLK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16N4O2/c1-13-11-15(27-21-17-6-10-26-18(17)5-7-23-21)3-4-16(13)20-14(2)24-12-19-22-8-9-25(19)20/h3-12H,1-2H3
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| Chemical Name |
4-[3-methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenoxy]furo[3,2-c]pyridine
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| Synonyms |
PF-06256142; PF 06256142; PF06256142
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| HS Tariff Code |
2934.99.03.00
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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: ~200 mg/mL (~561.2 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (14.03 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 50.0 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: ≥ 5 mg/mL (14.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 5 mg/mL (14.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8060 mL | 14.0300 mL | 28.0599 mL | |
| 5 mM | 0.5612 mL | 2.8060 mL | 5.6120 mL | |
| 10 mM | 0.2806 mL | 1.4030 mL | 2.8060 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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