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

  • J Med Chem. 2012 Sep 13;55(17):7849-61. doi: 10.1021/jm3009103.
Martin H Bolli  1 ,  Christoph Boss ,  Christoph Binkert ,  Stephan Buchmann ,  Daniel Bur ,  Patrick Hess ,  Marc Iglarz ,  Solange Meyer ,  Josiane Rein ,  Markus Rey ,  Alexander Treiber ,  Martine Clozel ,  Walter Fischli ,  Thomas Weller
Affiliations
  • 1. Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. [email protected]
PMID: 22862294 DOI: 10.1021/jm3009103
Abstract

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.