473537-03-0Relevant articles and documents
The discovery of N -[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]- N ′-propylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist
Bolli, Martin H.,Boss, Christoph,Binkert, Christoph,Buchmann, Stephan,Bur, Daniel,Hess, Patrick,Iglarz, Marc,Meyer, Solange,Rein, Josiane,Rey, Markus,Treiber, Alexander,Clozel, Martine,Fischli, Walter,Weller, Thomas
supporting information, p. 7849 - 7861 (2012/10/29)
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 ETA 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.
The use of sulfonylamido pyrimidines incorporating an unsaturated side chain as endothelin receptor antagonists
Bolli, Martin H.,Boss, Christoph,Clozel, Martine,Fischli, Walter,Hess, Patrick,Weller, Thomas
, p. 955 - 959 (2007/10/03)
A series of compounds structurally related to bosentan 1 featuring an unsaturated side chain at position 6 of the core pyrimidine have been studied for their potential to block the ETA and ETB receptor. Incorporation of a 2-butyne-1,4-diol linker bearing a pyridyl carbamoyl moiety led to in vitro highly potent endothelin receptor antagonists (e.g., 70 and 75). The propargyl derivative 26 significantly reduced blood pressure in in vivo model studies with hypertensive salt-sensitive Dahl rats.
