title: The use of sulfonylamido pyrimidines incorporating an unsaturated side chain as endothelin receptor antagonists.
abstract: 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 ET(A) and ET(B) 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.
authors.affiliation: Drug Discovery Chemistry and Preclinical Research, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil/BL, 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: Martine
authors.initials: M
authors.lastname: Clozel
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Thomas
authors.initials: T
authors.lastname: Weller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D016466:CHO Cells; D006224:Cricetinae; D004195:Disease Models, Animal; D016903:Drug Monitoring / Q000379:methods; D065128:Endothelin Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D000077300:Bosentan