2. Academic Validation
  3. 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

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

Affiliation

  • 1 Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. martin.bolli@actelion.com
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.

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