Key result
Macitentan was discovered as a potent dual endothelin receptor antagonist with high in vivo efficacy in hypertensive rats.
The medicinal chemistry program starting from bosentan led to the discovery of macitentan, a potent dual endothelin receptor antagonist with high oral efficacy that subsequently completed phase III trials for pulmonary arterial hypertension.
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Supports macitentan advancement from rat models; leaves open human efficacy confirmation in pulmonary arterial hypertension.
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.
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Bolli et al. (2012) studied Hypertension / Pulmonary arterial hypertension. Macitentan was evaluated. Macitentan was discovered as a potent dual endothelin receptor antagonist with high in vivo efficacy in hypertensive rats.
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