Macitentan

Macitentan

Clinical data
Trade names	Opsumit
Pregnancy category	US: X (Contraindicated)
Routes of administration	Oral
ATC code	C02KX04 (WHO)
Legal status
Legal status	US: ℞-only (FDA approved drug)
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
Synonyms	ACT-064992
CAS Number	441798-33-0
PubChem CID	16004692
ChemSpider	13134960
ChEBI	CHEBI:76607
Chemical and physical data
Formula	C19H20Br2N6O4S
Molar mass	588.273 g/mol
3D model (Jmol)	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 (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, 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.

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. 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.

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.

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.