1. Academic Validation
  2. From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective

From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective

  • Bioorg Med Chem Lett. 2016 Aug 1;26(15):3381-94. doi: 10.1016/j.bmcl.2016.06.014.
Christoph Boss 1 Martin H Bolli 2 John Gatfield 2
Affiliations

Affiliations

  • 1 Drug Discovery and Preclinical Research, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil/BL, Switzerland. Electronic address: christoph.boss@actelion.com.
  • 2 Drug Discovery and Preclinical Research, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil/BL, Switzerland.
Abstract

The endothelin Peptides bind to two receptors found on cells of vasculature and in tissues. While the endothelin-A (ETA)-receptor is predominantly expressed in vascular smooth muscle cells, the endothelin-B (ETB)-receptor is also found in endothelial cells, fibroblasts, and neuronal cells. Activation of the endothelin system plays a driving role in several chronic cardiovascular diseases and several Endothelin Receptor antagonists (ERAs) (bosentan (6), ambrisentan (83) and macitentan (43)) have successfully been introduced as oral treatments for the life threatening condition of pulmonary arterial hypertension (PAH). This digest highlights the medicinal chemistry of the pyrimidine based ERAs 6 and 43 and describes the story that started with bosentan and culminated in macitentan (43). A condensed overview of the competitive landscape in the field of ERAs puts the different strategies and tactics applied by the medicinal chemists involved in this endeavor into perspective.

Keywords

Endothelin; Endothelin receptor antagonists (ERA); G-protein-coupled receptor (GPCR); Macitentan; Pulmonary arterial hypertension (PAH); Pyrimidine; Sulfamide.

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