Repositioning Candidate Details
| Candidate ID: | R1189 |
| Source ID: | DB08932 |
| Source Type: | approved |
| Compound Type: | small molecule |
| Compound Name: | Macitentan |
| Synonyms: | -- |
| Molecular Formula: | C19H20Br2N6O4S |
| SMILES: | CCCNS(=O)(=O)NC1=C(C(OCCOC2=NC=C(Br)C=N2)=NC=N1)C1=CC=C(Br)C=C1 |
| Structure: |
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| DrugBank Description: | Macitentan is a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension. It was first approved by the FDA in 2013. Macitentan differs from its predecessor due to its lower risk of hepatotoxicity. |
| CAS Number: | 441798-33-0 |
| Molecular Weight: | 588.273 |
| DrugBank Indication: | Macitentan is indicated for the treatment of WHO group 1 pulmonary arterial hypertension (PAH) both alone and in combination with tadalafil. |
| DrugBank Pharmacology: | Macitentan acts primarily by reducing vasoconstriction and cell proliferation due to endothelin overexpression. |
| DrugBank MoA: | Macitentan is an antagonist which binds to the endothelin A and B receptors (E<sub>A</sub> and E<sub>B</sub>) and blocks signaling from endothelin-1 and -2. Pulmonary arterial hypertension has many different mechanisms which contribute to the development of endothelial dysfunction including elevated cytosolic calcium, genetic factors, epigenetic changes, and mitochondrial dysfunction. The focus of macitentan's mechanism relates to the role of overexpressed endothelin from the vascular endothelium. Endothelins are released in both a constitutive fashion from secretory vesicles and in response to stimuli via Weibel-Palade storage granules. Endothelins bind to the E<sub>A</sub> and E<sub>B</sub> receptors, with endothelins -1 and -2 having more affinity than endothelin-3. Binding to the Gq coupled E<sub>A</sub> receptor triggers Ca2+ release from the sarcoplasmic reticulum of smooth muscle cells via the phospholipase C (PLC) pathway. Downstream protein kinase C activation may also contribute to increased Ca2+ sensitivity of the contractile apparatus. E<sub>A</sub> receptor activation is also known to contribute to pulmonary artery smooth muscle cell proliferation. The binding of endothelins to the E<sub>B</sub> receptors acts in opposition to E<sub>A</sub> signaling by activating the same PLC cascade in endothelial cells to activate endothelial nitric oxide synthase. The subsequent release of nitric oxide produces vasodilation through the cyclic guanosine monophosphate cascade. Despite the greater presence of E<sub>B</sub> receptors on endothelial cells, they are still present on smooth muscle cells and may contribute to cell proliferation through the same mechanisms as E<sub>A</sub> receptors. Macitentan is thought to provide its therapeutic effect primarily via blocking signaling through E<sub>A</sub> which produces both decreased vasoconstriction via reduced smooth muscle cell contractility and attenuation of the hyperproliferation of smooth muscle cells found in PAH. Blockade of E<sub>B</sub> is less likely to contribute to a therapeutic effect as this signaling is responsible for the counter-regulatory vasodilatory signal. |
| Targets: | Endothelin-1 receptor antagonist; Endothelin B receptor antagonist |
| Inclusion Criteria: | Indication associated |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs |
|---|
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T03 | Peroxisome proliferator-activated receptor alpha | PPARA | agonist | Nuclear hormone receptor | Q07869 | PPARA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| T21 | Diacylglycerol O-acyltransferase 2 | DGAT2 | inhibitor | Enzyme | Q96PD7 | DGAT2_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I12 | 10763 | Hypertension | An artery disease characterized by chronic elevated blood pressure in the arteries. https://en.wikipedia.org/wiki/Hypertension, https://www.ncbi.nlm.nih.gov/pubmed/24352797 | disease of anatomical entity/ cardiovascular system disease/vascular disease/ artery disease | Details |