Macitentan
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MedKoo CAT#: 205912

CAS#: 441798-33-0

Description: Macitentan (trade name Opsumit) is an endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH). The other two ERAs marketed as of 2014 are bosentan and ambrisentan. Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB. However, macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype. The drug received approval from the U.S. Food and Drug Administration (FDA) on October 13, 2013.


Chemical Structure

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Macitentan
CAS# 441798-33-0

Theoretical Analysis

MedKoo Cat#: 205912
Name: Macitentan
CAS#: 441798-33-0
Chemical Formula: C19H20Br2N6O4S
Exact Mass: 585.96335
Molecular Weight: 588.27
Elemental Analysis: C, 38.79; H, 3.43; Br, 27.17; N, 14.29; O, 10.88; S, 5.45

Price and Availability

Size Price Availability Quantity
100.0mg USD 150.0 Same day
200.0mg USD 250.0 Same day
500.0mg USD 450.0 Same day
1.0g USD 650.0 Same day
2.0g USD 950.0 Same day
5.0g USD 1450.0 Same day
10.0g USD 2650.0 Same day
20.0g USD 3650.0 Same day
50.0g USD 4850.0 Same day
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Synonym: ACT-064992; ACT 064992; ACT064992; Macitentan; brand name: Opsumit.

IUPAC/Chemical Name: N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]-N'- propylsulfamide

InChi Key: JGCMEBMXRHSZKX-UHFFFAOYSA-N

InChi Code: InChI=1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27)

SMILES Code: O=S(NCCC)(NC1=NC=NC(OCCOC2=NC=C(Br)C=N2)=C1C3=CC=C(Br)C=C3)=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Macitentan (ACT-064992) is a dual ETA/ETB (endothelin) receptor antagonist with IC50 of 0.5 nM/391 nM.
In vitro activity: In vitro, macitentan reversed the glycolytic metabolic switch of PAH–PASMC and decreased PAH–PASMC proliferation. While macitentan did not affect oxPhox, proliferation, and apoptosis of PAH-PA endothelial cells (PAECs), it significantly improved their angiogenic capacity (tube formation assay). Exposure of control PASMC and PAEC to ET-1 fully mimicked the PAH cells phenotype, thus confirming that ET-1 is implicated in both metabolism and angiogenesis abnormalities in PAH. Reference: Pulm Circ. 2018 Jan-Mar;8(1):2045893217741429. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731731/
In vivo activity: Dysregulated metabolism and rarefaction of the capillary network play a critical role in pulmonary arterial hypertension (PAH) etiology. They are associated with a decrease in perfusion of the lungs, skeletal muscles, and right ventricle (RV). Previous studies suggested that endothelin-1 (ET-1) modulates both metabolism and angiogenesis. Five weeks after disease induction, Sugen/hypoxic rats presented severe PAH with pulmonary artery (PA) remodeling, RV hypertrophy and capillary rarefaction in the lungs, RV, and skeletal muscles (microCT angiogram, lectin perfusion, CD31 staining). Two-week treatment with dual ETA/ETB receptors antagonist macitentan (30 mg/kg/d) significantly improved pulmonary hemodynamics, PA vascular remodeling, and RV function and hypertrophy compared to vehicle-treated animals (all P = 0.05). Moreover, macitentan markedly increased lung, RV and quadriceps perfusion, and microvascular density (all P = 0.05). Reference: Pulm Circ. 2018 Jan-Mar;8(1):2045893217741429. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731731/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 75.0 127.49
DMF 33.0 56.1
DMF:PBS (pH 7.2) (1:7) 0.12 0.2

Preparing Stock Solutions

The following data is based on the product molecular weight 588.27 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Corallo C, Pecetti G, Iglarz M, Volpi N, Franci D, Montella A, D' Onofrio F, Nuti R, Giordano N. Macitentan slows down the dermal fibrotic process in systemic sclerosis: in vitro findings. J Biol Regul Homeost Agents. 2013 Apr-Jun;27(2):455-62. PMID: 23830395. 2. Nadeau V, Potus F, Boucherat O, Paradis R, Tremblay E, Iglarz M, Paulin R, Bonnet S, Provencher S. Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension. Pulm Circ. 2018 Jan-Mar;8(1):2045893217741429. doi: 10.1177/2045893217741429. Epub 2017 Oct 24. PMID: 29064353; PMCID: PMC5731731.
In vitro protocol: 1. Corallo C, Pecetti G, Iglarz M, Volpi N, Franci D, Montella A, D' Onofrio F, Nuti R, Giordano N. Macitentan slows down the dermal fibrotic process in systemic sclerosis: in vitro findings. J Biol Regul Homeost Agents. 2013 Apr-Jun;27(2):455-62. PMID: 23830395. 2. Nadeau V, Potus F, Boucherat O, Paradis R, Tremblay E, Iglarz M, Paulin R, Bonnet S, Provencher S. Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension. Pulm Circ. 2018 Jan-Mar;8(1):2045893217741429. doi: 10.1177/2045893217741429. Epub 2017 Oct 24. PMID: 29064353; PMCID: PMC5731731.
In vivo protocol: 1. Nadeau V, Potus F, Boucherat O, Paradis R, Tremblay E, Iglarz M, Paulin R, Bonnet S, Provencher S. Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension. Pulm Circ. 2018 Jan-Mar;8(1):2045893217741429. doi: 10.1177/2045893217741429. Epub 2017 Oct 24. PMID: 29064353; PMCID: PMC5731731.

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1: Shinohara T, Sawada H, Otsuki S, Yodoya N, Kato T, Ohashi H, Zhang E, Saitoh S, Shimpo H, Maruyama K, Komada Y, Mitani Y. Macitentan reverses early obstructive pulmonary vasculopathy in rats: Early intervention in overcoming the survivin-mediated resistance to apoptosis. Am J Physiol Lung Cell Mol Physiol. 2014 Dec 24:ajplung.00129.2014. doi: 10.1152/ajplung.00129.2014. [Epub ahead of print] PubMed PMID: 25539851.

2: Kholdani CA, Fares WH, Trow TK. Macitentan for the treatment of pulmonary arterial hypertension. Vasc Health Risk Manag. 2014 Nov 25;10:665-73. doi: 10.2147/VHRM.S33904. eCollection 2014. PubMed PMID: 25473292; PubMed Central PMCID: PMC4251661.

3: Channick RN, Delcroix M, Ghofrani HA, Hunsche E, Jansa P, Le Brun FO, Mehta S, Pulido T, Rubin LJ, Sastry BK, Simonneau G, Sitbon O, Souza R, Torbicki A, Galiè N. Effect of Macitentan on Hospitalizations: Results From the SERAPHIN Trial (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome). JACC Heart Fail. 2014 Nov 11. pii: S2213-1779(14)00384-9. doi: 10.1016/j.jchf.2014.07.013. [Epub ahead of print] PubMed PMID: 25457902.

4: Tullos NA, Stewart NJ, Davidovich R, Chade AR. Chronic blockade of endothelin A and B receptors using macitentan in experimental renovascular disease. Nephrol Dial Transplant. 2014 Nov 21. pii: gfu361. [Epub ahead of print] PubMed PMID: 25438341.

5: Said K. Macitentan in pulmonary arterial hypertension: The SERAPHIN trial. Glob Cardiol Sci Pract. 2014 Jun 18;2014(2):26-30. doi: 10.5339/gcsp.2014.20. eCollection 2014. PubMed PMID: 25405173; PubMed Central PMCID: PMC4220429.

6: Sood N. Macitentan for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2014 Dec;15(18):2733-9. doi: 10.1517/14656566.2014.980403. Epub 2014 Nov 11. PubMed PMID: 25385427.

7: Temple IP, Monfredi O, Quigley G, Schneider H, Zi M, Cartwright EJ, Boyett MR, Mahadevan VS, Hart G. Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model. Int J Cardiol. 2014 Dec 15;177(2):423-8. doi: 10.1016/j.ijcard.2014.09.005. Epub 2014 Oct 11. PubMed PMID: 25305681; PubMed Central PMCID: PMC4251701.

8: Gatfield J, Mueller Grandjean C, Bur D, Bolli MH, Nayler O. Distinct ETA receptor binding mode of macitentan as determined by site directed mutagenesis. PLoS One. 2014 Sep 16;9(9):e107809. doi: 10.1371/journal.pone.0107809. eCollection 2014. PubMed PMID: 25226600; PubMed Central PMCID: PMC4166607.

9: Kunita-Takanezawa M, Abe K, Hirooka Y, Kuwabara Y, Hirano K, Oka M, Sunagawa K. Novel dual endothelin receptor antagonist macitentan reverses severe pulmonary arterial hypertension in rats. J Cardiovasc Pharmacol. 2014 Nov;64(5):473-80. doi: 10.1097/FJC.0000000000000141. PubMed PMID: 25084082.

10: Dhillon S. Macitentan: a review of its use in patients with pulmonary arterial hypertension. Drugs. 2014 Sep;74(13):1495-507. doi: 10.1007/s40265-014-0266-9. PubMed PMID: 25060980.

11: DuBrock HM, Channick RN. Macitentan for the treatment of pulmonary arterial hypertension. Expert Rev Respir Med. 2014 Aug;8(4):393-9. doi: 10.1586/17476348.2014.937708. Epub 2014 Jul 6. PubMed PMID: 24998329.

12: Spikes L, Williamson T, Satterwhite L. Macitentan for the treatment of pulmonary arterial hypertension. Drugs Today (Barc). 2014 Jun;50(6):401-6. doi: 10.1358/dot.2014.50.6.2146837. Review. PubMed PMID: 24983588.

13: Sidharta PN, van Giersbergen PL, Wolzt M, Dingemanse J. Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects. Br J Clin Pharmacol. 2014 Nov;78(5):1035-42. doi: 10.1111/bcp.12447. PubMed PMID: 24962473; PubMed Central PMCID: PMC4243877.

14: Ahn LY, Kim SE, Yi S, Dingemanse J, Lim KS, Jang IJ, Yu KS. Pharmacokinetic-pharmacodynamic relationships of macitentan, a new endothelin receptor antagonist, after multiple dosing in healthy Korean subjects. Am J Cardiovasc Drugs. 2014 Oct;14(5):377-85. doi: 10.1007/s40256-014-0081-4. PubMed PMID: 24906252.

15: Sidharta PN, Dietrich H, Dingemanse J. Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Clin Drug Investig. 2014 Aug;34(8):545-52. doi: 10.1007/s40261-014-0207-0. PubMed PMID: 24861134.

16: Clarke M, Walter C, Agarwal R, Kanwar M, Benza RL. Macitentan (Opsumit) for the treatment of pulmonary arterial hypertension. Expert Rev Clin Pharmacol. 2014 Jul;7(4):415-21. doi: 10.1586/17512433.2014.919849. Epub 2014 May 22. PubMed PMID: 24851934.

17: Lindegger N, Sidharta PN, Reseski K, Dingemanse J. Macitentan, a dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension, does not affect cardiac repolarization in healthy subjects. Pulm Pharmacol Ther. 2014 Oct;29(1):41-8. doi: 10.1016/j.pupt.2014.04.007. Epub 2014 May 9. PubMed PMID: 24813561.

18: Treiber A, Äänismaa P, de Kanter R, Delahaye S, Treher M, Hess P, Sidharta P. Macitentan does not interfere with hepatic bile salt transport. J Pharmacol Exp Ther. 2014 Jul;350(1):130-43. doi: 10.1124/jpet.114.214106. Epub 2014 Apr 25. PubMed PMID: 24769543.

19: Steriade A, Seferian A, Jaïs X, Savale L, Jutant EM, Parent F, Sitbon O, Humbert M, Simonneau G, Montani D. The potential for macitentan, a new dual endothelin receptor antagonist, in the treatment of pulmonary arterial hypertension. Ther Adv Respir Dis. 2014 Apr 11;8(3):84-92. [Epub ahead of print] Review. PubMed PMID: 24728960.

20: Macitentan (Opsumit) for pulmonary arterial hypertension. Med Lett Drugs Ther. 2014 Feb 17;56(1436):15-6. PubMed PMID: 24663031.

Macitentan

100.0mg / USD 150.0


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