Friday, February 12, 2016

Macitentan | Endothelin Receptor Antagonist | Treatment for Pulmonary Arterial Hypertension | Dual ETA and ETB Inhibitor

Macitentan [N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide] is a novel orally available, small molecule dual endothelin receptor antagonist (ERA) with sustained receptor binding properties developed for the treatment of pulmonary arterial hypertension (PAH) [1].

Macitentan: 2D and 3D Structure

Macitentan is designed by modifying the structure of Bosentan (a previously launched ERA), with the aim of improving efficacy and safety compared with other ERAs. Like Bosentan, Macitentan retains the dual (ETA and ETB) ERA antagonism but with relatively better drug profile.

What are Endothelins?
Endothelin (ET) is an extremely potent blood vessel constricting substance that is secreted by endothelial cells. Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides produced and active in almost all tissues. Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions. They participate in bronchoconstriction and regulate neu-retransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation. 

Endothelins convey their action through binding to two G-protein coupled receptors called ETA and ETB. Among the three isopeptides, ET-1 appears to be the key player in the cardiovascular system. ET-2 and ET-3 are specifically expressed in the gastrointestinal tract and the brain, respectively. On the vascular side, ETA receptors are mainly expressed on smooth muscle cells, mediating vasoconstriction, while ETB receptors expressed on endothelial cells and smooth muscle cells cause vasodilation and vasoconstriction, respectively.

Both ETA and ETB receptors are involved in mediating ET-1 deleterious effects in diseases such as chronic heart failure, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, or kidney disease. Furthermore, in many pathological situations, the ET system is up-regulated and a change in the ETA/ETB expression ratio in favor of ETB is observed in diseased tissue. Several studies corroborate that increased activity of the ET system in tissue correlates with disease severity. 

ET-1 is implicated in several forms of vascular disease making it a valid target for the treatment of pulmonary vascular diseases such as PAH. ET-1 is upregulated in patients with PAH and influences pathological changes, including vasoconstriction, proliferation and fibrosis in the lung via two ET receptor subtypes, ETA and ETB, to which it binds with high affinity [2, 3].

Macitentan targets ETA and ETB receptors
Macitentan targets ETA and ETB receptors with a high tissue affinity and prevents ET-1 from binding to both receptors. Macitentan exhibits a pKa value of 6.2 and consequently has a relatively high percentage of nonionized form in an aqueous environment at physiological pH 7.4 compared with other endothelin receptor antagonists (Bosentan, Ambrisentan =  5.1, 3.5 respectively).
Furthermore, chemical modifications resulting in increased log D values also lead to increased affinity for the tissue because log D is considered to be an indicator of distribution between plasma and tissue.  Macitentan shows a distribution of 800 to 1 between octanol and aqueous buffer and thus a good distribution to lipids and tissues. Only the nonionized form is able to cross cell membranes, and an increased concentration gradient of the nonionized molecule drives the net flux across lipophilic cell membranes. In comparison, Bosentan also has a preferred affinity for the lipophilic phase as shown by a distribution of 20 to 1, whereas ambrisentan has more affinity for the aqueous milieu than for lipids. Overall, Macitentan presents a 40- and 2000-fold increased affinity for the lipid phase versus Bosentan and Ambrisentan, respectively.
Affinity of Mmacitentan and its major metabolite ACT-132577 for the ET receptors was assessed in microsomal membranes of Chinese hamster ovary cells stably overexpressing human ETA and ETB receptors. Macitentan inhibited binding of 125I-ET-1 to recombinant ETA receptors, with a mean IC50 value of 0.5 ± 0.2 nM (n = 17). The mean IC50 value for ETB receptors was 391 ± 182 nM (n = 17). For ACT-132577, the mean IC50 values for ETA and ETB receptors were 3.4 ± 0.4 nM (n = 4) and 987 ± 185 nM (n = 9), respectively [2].

ACT-132577: 2D and 3D Structure

Approval and Dosages
Macitentan (Tradename: Opsumit) was discovered by Actelion Pharmaceuticals Ltd. In 2010, Actelion licensed the compound to Nippon Shinyaku in Japan for the treatment of pulmonary arterial hypertension (PAH). In October 2013, oral macitentan 10 mg once daily received its first global approval in the US, followed closely by Canada. The drug has also received a positive opinion in the EU from the Committee for Medicinal Products for Human Use for the treatment of PAH, and is under regulatory review in several other countries for the same indication.

The pharmacological potency of Macitentan is greater than that of Bosentan in vivo, as the increase in ET-1 plasma levels was achieved at a Macitentan dose that was 10-fold lower.

Macitentan Synthesis
WO2002053557A1: This patent is the first reported synthesis route for Macitentan. Ref. 5 uses the same procedure and prepares specific molecules. The latter patent appears to be the industrial process. Also see Ref. 3 which reports the same procedure.

Intermediate synthesis:

Final synthesis:


Common name: Actelion-1; ACT-064992; ACT064992; ACT 064992
Trademarks: Opsumit
Molecular Formula: C19H20Br2N6O4S
CAS Registry Number: 441798-33-0
CAS Name: N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide
Molecular Weight: 588.273
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)
Mechanism of Action: Dual endothelin (ET) A and B receptor antagonist
Activity: Treatment of Pulmonary Arterial Hypertension; Treatment of PAH; Cardiac Therapy; Antihypertensives; Antineoplastic Agents; Respiratory System Products
Status: Launched 2013 (US, EU)
Chemical Class: Bromobenzenes; Pyrimidines; Small-molecules; Sulfamides
Originator: Actelion Pharmaceuticals/Nippon Shinyaku


1H NMR (Estimated) for Macitentan
Experimental: 1H NMR (CDCl3): δ 8.51 (s, 2 H), 8.49 (s, 1 H), 7.58-7.63 (m, 2 H), 7.16-7.21 (m, 2 H), 6.88 (s, 1 H), 5.61 (t, J = 6.2 Hz, 1 H), 4.72-4.76 (m, 2 H), 4.62-4.66 (m, 2 H), 2.99 (q, J = 6.8 Hz, 2 H), 1.61 (h, J = 7.3 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).

13C NMR (Estimated) for Macitentan
Experimental: 13C NMR (CDCl3): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3.

Sideeffects: The adverse events (AEs) from various clinical trials show that nasopharyngitis, headache and anaemia occurred in a significantly higher proportion of patients in the Macitentan groups than in the placebo group. Participants have also reported worsening of PAH, upper respiratory tract infection, peripheral oedema, right ventricular failure but in all these cases the placebo group too has reported the same event with nearly the same numbers.

As with other available ERAs, the label carries a Boxed Warning stating that the drug should not be used in pregnant women due to harmful effects on the developing foetus.

1. Patel, T.; et. al. Macitentan: first global approval. Drugs 2014, 74(1), 127-133.
2. Clozel, M.; et. al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther 2008, 327(3), 736-745.
3. Bolli, M. H.; et. al. The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem 2012, 55(17), 7849-7861.
4. Bolli, M.; et. al. Novel sulfamides and their use as endothelin receptor antagonists. WO2002053557A1
5. Bolli, M.; et. al. Sulfamides as endothelin receptor antagonists for the treatment of cardiovascular diseases. WO2006051502A2