The widespread actions of endothelin-1 (ET-1) and its receptors, ETA and ETB, have led to extreme interest in endothelin antagonists for the treatment of various cardiovascular and other disorders.
The first commercially available antagonist, bosentan, blocks both receptors and has been successfully marketed for the treatment
of pulmonary arterial hypertension. Similarly, selective ETA receptor antagonists, such as ambrisentan and sitaxentan, have been approved for the same indication in most countries. However,
debate remains as to whether selective ETA blockade or dual ETA/B blockade would provide a therapeutic advantage. Despite the demonstrated clinical utility of endothelin receptor antagonists,
there is much room for improvement in the “-sentan” class of drugs. Recently, investigators reported the development of a
new dual endothelin receptor antagonist, macitentan. A specific goal of the drug discovery process, of which macitentan was
the end product, was to improve tissue-targeting by selecting lipophilic agents for development. This is a potentially exciting
discovery if it can be demonstrated that such compounds partition into local tissue environments to obtain a more preferable
pharmacological profile in targeting the largely autocrine-paracrine endothelin system.
