Chemistry:Macitentan

Short description: Chemical compound

Macitentan

Clinical data
Trade names	Opsumit
Other names	ACT-064992
AHFS/Drugs.com	Monograph
MedlinePlus	a615033
License data	EU EMA: by INN US DailyMed: Macitentan
Pregnancy category	AU: X (High risk)
Routes of administration	By mouth
ATC code	C02KX04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only
Pharmacokinetic data
Metabolism	Hydrolysis, oxidation (CYP3A4)
Excretion	2/3 urine, 1/3 faeces
Identifiers
IUPAC name N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide
CAS Number	441798-33-0
PubChem CID	16004692
DrugBank	DB08932
ChemSpider	13134960
UNII	Z9K9Y9WMVL
KEGG	D10135
ChEBI	CHEBI:76607
ChEMBL	ChEMBL2103873
Chemical and physical data
Formula	C19H20Br2N6O4S
Molar mass	588.28 g·mol−1
3D model (JSmol)	Interactive image
SMILES Brc1ccc(cc1)c3c(ncnc3OCCOc2ncc(Br)cn2)NS(=O)(=O)NCCC
InChI 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) Key:JGCMEBMXRHSZKX-UHFFFAOYSA-N

Macitentan, sold under the brand name Opsumit, is an endothelin receptor antagonist (ERA) developed by Actelion and 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, ET_A and ET_B. 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.

Macitentan is available as a generic medication in the United States as of April 2021.

Adverse effects

The FDA has issued a black box warning for macitentan for embryo-fetal toxicity. It is only available to females in the U.S through a risk evaluation and mitigation strategy (REMS) program.

Mechanism of action

Endothelin and endothelin receptors

Endothelin (ET) is an extremely potent blood vessel constricting substance that is secreted by endothelial cells. In the lungs, the most common ET form released is ET-1. ET-1 release can occur through both constitutive and non-constitutive pathways. Upon release, ET-1 can bind to the ET receptors that are expressed on arterial smooth muscle cells and fibroblasts in the lungs. ET receptors are G protein coupled receptors and, when activated, lead to an increase in intracellular calcium levels via the Gαq signaling pathway. There are two receptor subtypes that endothelin will bind to: ETA and ETB. ETA is associated with cell growth and vasoconstriction while ETB is responsible for anti-proliferation of cells, vasodilation and ET-1 clearance. The rise in intracellular calcium leads to contraction of the arterial smooth muscle, as well as vascular remodelling due to cell proliferation. Prolonged constriction and fibrosis are factors in the pathogenesis of PAH.

Role of macitentan

Macitentan blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors. Blocking of the ETA receptor subtype seems to be of more importance in the treatment of PAH than blocking of ETB, likely because there are higher numbers of ETA receptors than ETB receptors in pulmonary arterial smooth muscle cells. The blocking of Endothelin 1 leads to vasodilation and decreases the proliferation of cells in the vessels of the artries which contributes to the narrowing and leads to the pulmonary arterial hypertension.

Pharmacokinetics

Macitentan is taken as a 10 mg oral dose once a day. Its half-life in humans is about 16 hours and steady state is reached by the third day of administration. It is absorbed slowly into the plasma. Macitentan dealkylates into the active metabolite aprocitentan (ACT-132577), which reaches its peak plasma concentration about 30 hours after the first dose is administered, and has a half-life of approximately 48 hours. Although aprocitentan has a lower affinity for the ET receptors than its parent compound, It maintains higher plasma concentrations than macitentan. Both compounds can be excreted from the body through the urine or feces.

Co-administration of ciclosporin has only a slight effect on the concentrations of macitentan and its active metabolite, while rifampicin decreases the area under the curve (AUC) of the drug's blood plasma concentration by 79%, and ketoconazole approximately doubles it. This corresponds to the finding that macitentan is mainly metabolised via the liver enzyme CYP3A4.

Aprocitentan, the active metabolite of macitentan

Experimental pharmacokinetics

Macitentan has slow association kinetics. Its potency increases 6.3-fold when it is pre-incubated with pulmonary arterial smooth muscle cells for 120 minutes compared to 10 minutes with pulmonary arterial smooth muscle cells. Macitentan also has a high receptor occupancy half-life (approximately 17 minutes) compared to bosentan (approximately 70 seconds) and ambrisentan (approximately 40 seconds). This increased receptor occupancy half-life allows macitentan to act as a non-competitive antagonist of ET receptors. Bosentan and ambrisentan are both competitive antagonists.

External links

• "Macitentan". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/macitentan.