title: Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension.
abstract: OBJECTIVE
  The endothelin (ET) system is a tissular system, as the production of ET isoforms is mostly autocrine or paracrine. Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. To determine if these features translate into improved efficacy in vivo, a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual ETA/ETB receptor antagonist, bosentan, which does not display sustained receptor occupancy and shows less tissue distribution.
  
  
  METHODS
  After establishing dose-response curves of both compounds in conscious, hypertensive Dahl salt-sensitive and pulmonary hypertensive bleomycin-treated rats, macitentan was administered on top of the maximal effective dose of bosentan.
  
  
  RESULTS
  In hypertensive rats, macitentan 30 mg/kg further decreased mean arterial blood pressure (MAP) by 19 mm Hg when given on top of bosentan 100 mg/kg (n=9, p<0.01 vs. vehicle). Conversely, bosentan given on top of macitentan failed to induce an additional MAP decrease. In pulmonary hypertensive rats, macitentan 30 mg/kg further decreased mean pulmonary artery pressure (MPAP) by 4 mm Hg on top of bosentan (n=8, p<0.01 vs. vehicle), whereas a maximal effective dose of bosentan given on top of macitentan did not cause any additional MPAP decrease.
  
  
  CONCLUSIONS
  The add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy.
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland. Electronic address: marc.iglarz@actelion.com.
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bossu
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wanner
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Bortolamiol
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rey
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
authors.forename: Martine
authors.initials: M
authors.lastname: Clozel
mesh_terms: D000818:Animals; D001761:Bleomycin; D000077300:Bosentan; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy*; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020303:Rats, Inbred Dahl; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D001761:Bleomycin; D000077300:Bosentan; C533860:macitentan
keywords: Blood pressure; Endothelin; Pharmacology; Pulmonary hypertension; Rat