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.
Physicochemical Properties
| Molecular Formula | C21H16N4O2 |
| Molecular Weight | 356.37734413147 |
| Exact Mass | 356.13 |
| Elemental Analysis | C, 70.77; H, 4.53; N, 15.72; O, 8.98 |
| CAS # | 1609583-14-3 |
| Related CAS # | (Rac)-PF-06256142; 1609580-97-3; (R)-PF-06256142; 1609583-15-4 |
| PubChem CID | 75201901 |
| Appearance | Solid powder |
| LogP | 4.3 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 27 |
| Complexity | 520 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | HWAIAGZSWHOLLK-UHFFFAOYSA-N |
| 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 |
| Chemical Name | 4-[3-methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenoxy]furo[3,2-c]pyridine |
| Synonyms | PF-06256142; PF 06256142; PF06256142 |
| HS Tariff Code | 2934.99.03.00 |
| 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 | Human D1 Receptor ( IC50 = 33 nM ) |
| 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]. |
| 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]. |
| Animal Protocol |
Rat 5.0 mg/kg for i.v.; 5 mg/kg for oral (Pharmacokinetic Analysis) Intravenous injection and oral administration |
| References |
[1]. Discovery and Lead Optimization of Atropisomer D1 Agonists with Reduced Desensitization. J Med Chem. 2018 Nov 15. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~200 mg/mL (~561.2 mM) |
| 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. 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. 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 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 | 2.8060 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 |