Aprocitentan D4 (ACT132577 D4; ACT-132577 D4) is the tetra-deuterate form of Aprocitentan, which is a major active metabolite of Macitentan (a dual ETA/ETB antagonist).
Physicochemical Properties
| Molecular Formula | C₁₆H₁₀D₄BR₂N₆O₄S |
| Molecular Weight | 550.22 |
| Exact Mass | 543.916 |
| CAS # | 1103522-45-7 |
| Related CAS # | Aprocitentan-d4 |
| PubChem CID | 25099191 |
| Appearance | White to off-white solid powder |
| LogP | 4.385 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 29 |
| Complexity | 597 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | 0 |
| InChi Key | DKULOVKANLVDEA-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C16H14Br2N6O4S/c17-11-3-1-10(2-4-11)13-14(24-29(19,25)26)22-9-23-15(13)27-5-6-28-16-20-7-12(18)8-21-16/h1-4,7-9H,5-6H2,(H2,19,25,26)(H,22,23,24) |
| Chemical Name | 5-(4-bromophenyl)-4-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-6-(sulfamoylamino)pyrimidine |
| 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 | The ET-1-induced rise in intracellular calcium in non-recombinant cells (primary human lung smooth muscle cells, rat aortic smooth muscle cell line A10, and mouse fibroblast cell line 3T3) is entirely inhibited by aproticitentan (ACT-132577) [1]. |
| ln Vivo | Aprocitentan (ACT-132577) has a longer half-life than its parent chemical and a volume of distribution larger than rats' plasma volumes [1]. The average recovery of Aprocitentan (ACT-132577) in rat plasma ranged from 82.6% to 90.6%, whereas its matrix effect in rat plasma varied from 101.4% to 115.2% [2]. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of aprocitentan during breastfeeding. Because aprocitentan is more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is 41 hours and it might accumulate in the infant. Because no information is available on the use of aprocitentan during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
| References |
[1]. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008 Dec;327(3):736-45. [2]. Pharmacokinetic study of ACT-132577 in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry. Int J Clin Exp Med. 2015 Oct 15;8(10):18420-6. |
| Additional Infomation |
ACT-132577 is a member of the class of sulfamides in which one of the amino groups of sulfonamide is substituted by a 5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl group. An active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. It has a role as an antihypertensive agent, an endothelin receptor antagonist, a drug metabolite and a xenobiotic metabolite. It is an aromatic ether, an organobromine compound, a member of pyrimidines and a member of sulfamides. It is functionally related to an ethylene glycol. Aprocitentan is under investigation in clinical trial NCT03541174 (A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its Safety). Drug Indication Treatment of hypertension |
Solubility Data
| Solubility (In Vitro) | DMSO : ~25 mg/mL (~45.77 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.58 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 (4.58 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 | 1.8175 mL | 9.0873 mL | 18.1745 mL | |
| 5 mM | 0.3635 mL | 1.8175 mL | 3.6349 mL | |
| 10 mM | 0.1817 mL | 0.9087 mL | 1.8175 mL |