PF-06282999 is a novel, potent and selective myeloperoxidase (MPO) inhibitor with the potential for the treatment of cardiovascular diseases. Robust inhibition of plasma MPO activity was demonstrated with PF-06282999 upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies. Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option.
Physicochemical Properties
| Molecular Formula | C13H12CLN3O3S |
| Molecular Weight | 325.77 |
| Exact Mass | 325.028 |
| CAS # | 1435467-37-0 |
| PubChem CID | 71571306 |
| Appearance | White to light yellow solid powder |
| Density | 1.5±0.1 g/cm3 |
| Index of Refraction | 1.694 |
| LogP | 1.31 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 21 |
| Complexity | 497 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | ICYNYWFGIDGBRD-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C13H12ClN3O3S/c1-20-10-3-2-7(14)4-8(10)9-5-12(19)16-13(21)17(9)6-11(15)18/h2-5H,6H2,1H3,(H2,15,18)(H,16,19,21) |
| Chemical Name | 2-[6-(5-chloro-2-methoxyphenyl)-4-oxo-2-sulfanylidenepyrimidin-1-yl]acetamide |
| Synonyms | PF-06282999; PF 06282999; PF06282999 |
| 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
| ln Vitro | PF-06282999 (Compound 8) is a strong and specific myeloperoxidase inhibitor. The IC50 value of 1.9 μM found in human whole blood testing is in good agreement with the expected EC50 value of 3.8 μM for the total concentration of PF-06282999 in plasma [2]. |
| ln Vivo | In humans and preclinical animals, PF-06282999 is moderately bound to plasma proteins. Mice, rats, dogs, monkeys, and humans had blood/plasma ratios of PF-06282999 of 1.1, 1.1, 0.91, 1.2, and 0.94, respectively, suggesting that PF-06282999 is dispersed equally in plasma and red blood cells [1]. More research was done on the in vivo pharmacokinetics of PF-06282999 in mice, rats, dogs, and monkeys. The results showed that it was medium with low CLp in the monkeys (10.3 mL/min/kg), and moderate with the rats (41.8 mL/min/kg). The four species' terminal plasma elimination half-lives (t1/2) varied from 0.75 to 3.3 hours. The urine of rats, dogs, and monkeys excretes about 26-32% of an intravenous dose of PF-06282999 unaltered. It has also been demonstrated to be well dispersed in these animals, with a steady-state volume of distribution (Vdss) in the range of 0.5 - mouse, rat, and 2.1 L/kg in dogs and monkeys. In mice, rats, dogs, and monkeys, oral administration of PF-06282999 results in rapid (Tmax=0.78-1.70 h) and well-absorbed drug with oral bioavailability values of 100%, 86%, 75%, and 76%, respectively [2]. |
| References |
[1]. Pharmacokinetics and Disposition of the Thiouracil Derivative PF-06282999, an Orally Bioavailable, Irreversible Inactivator of Myeloperoxidase Enzyme, Across Animals and Humans. Drug Metab Dispos. 2016 Feb;44(2):209-19. [2]. Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases. J Med Chem. 20. |
| Additional Infomation | Pf 06282999 is under investigation in clinical trial NCT01626976 (A Study To Assess The Safety, Tolerability And Pharmacokinetics Of PF-06282999 Administered Orally In Healthy Adult Subjects). |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~306.97 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.67 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. 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 (7.67 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 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: 2.5 mg/mL (7.67 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. 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 | 3.0697 mL | 15.3483 mL | 30.6965 mL | |
| 5 mM | 0.6139 mL | 3.0697 mL | 6.1393 mL | |
| 10 mM | 0.3070 mL | 1.5348 mL | 3.0697 mL |