Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

Abstract

The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.

Keywords: ambrisentan; atrasentan; bosentan; cancer; cerebral vasospasm; clazosentan; fibrotic disorders; macitentan; pain management; pulmonary arterial hypertension; renal disease; systemic scleroderma; zibotentan.

Figure 1

The canonical pathway of ET-1. Active ET-1 is synthesized from precursors via endothelin converting enzymes (ECE). ET-1 signals via two G protein-coupled receptors, ET_A and ET_B, both of which share the same G_q/11 signaling pathway. Activation of a receptor leads to the activation of phospholipase C (PLC), which processes the molecule phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ binds its receptor located on the sarcoplasmic reticulum (SR), followed by a release of Ca²⁺ into the cytosol. Arrows describe cause–effect relationships. The right panel is a zoom-in (big arrow) of the box region. CaM, calmodulin; MLCK, myosin light-chain kinase; PKC, protein kinase C; ROC, receptor-operated channel; RyR, ryanodine receptor; VOC, voltage-gated channel. Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0).

Figure 2

Chemical structures of ERAs.

Figure 3

(A) Involvement of ET-1 (yellow circles) in cancer progression and metastasis. (B) Postulated ET-1 receptor A signaling in tumor cells. Binding of ET-1 to the ET_A receptor induces VEGF (gray squares) and ET-1 expression by upregulation of HIF-1α. (C) Possible involvement of ET-1 receptor B on the regulation of HIF-1α stability. Arrows describe cause–effect relationships. Red lines indicate receptor antagonism of the respective ERAs. Akt, protein kinase B; β-arr., β-arrestin; CAF, cancer-associated fibroblast; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; Erk, extracellular signal-regulated kinase; FAK, focal adhesion kinase, ILK, integrin-linked kinase; MEK, Raf–mitogen-activated protein kinase (MAPK)/ERK kinase; MMP, matrix metallopeptidases; mTOR, mammalian target of rapamycin PI3K, phosphoinositide 3-kinase; Ras, rat sarcoma proto oncogene; TAM, tumor-associated macrophage; VEGF(R), vascular endothelial growth factor (receptor). Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0).

Figure 4

Pathological roles of ET-1 (yellow circles) and endothelin receptor signaling in different diseases. Arrows indicate cause–effect relationships. ANP, atrial natriuretic peptide; AVP, arginine vasopressin; GFR, glomerular filtration rate; RPF, renal plasma flow; SCAD, spontaneous coronary artery dissection; question mark, correlation not exactly known. Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0).