Starting from the structure of bosentan (1), we embarked on a medicinal 
chemistry program aiming at the identification of novel potent dual endothelin 
receptor antagonists with high oral efficacy. This led to the discovery of a 
novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 
17 (macitentan, ACT-064992) emerged as particularly interesting as it is a 
potent inhibitor of ET(A) with significant affinity for the ET(B) receptor and 
shows excellent pharmacokinetic properties and high in vivo efficacy in 
hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a 
long-term phase III clinical trial for pulmonary arterial hypertension.