title: 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.
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.
authors.affiliation: Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. martin.bolli@actelion.com
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bolli
authors.forename: Christoph
authors.initials: C
authors.lastname: Boss
authors.forename: Christoph
authors.initials: C
authors.lastname: Binkert
authors.forename: Stephan
authors.initials: S
authors.lastname: Buchmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.forename: Solange
authors.initials: S
authors.lastname: Meyer
authors.forename: Josiane
authors.initials: J
authors.lastname: Rein
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan